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CE: Namrta; HJH/201714; Total nos of Pages: 38;

HJH 201714

Original article 1

Reappraisal of European guid
elines on hypertensionmanagement: a European Society of Hypertension TaskForce documentGiuseppe Manciaa, Stephane Laurentb, Enrico Agabiti-Roseic,Ettore Ambrosionid, Michel Burniere, Mark J. Caulfieldf, Renata Cifkovag,Denis Clementh, Antonio Cocai, Anna Dominiczakj, Serap Erdinek,Robert Fagardl, Csaba Farsangm, Guido Grassin, Hermann Hallero,Antony Heagertyp, Sverre E. Kjeldsenq, Wolfgang Kiowskir, Jean Michel Mallions,Athanasios Manolist, Krzysztof Narkiewiczu, Peter Nilssonv, Michael H. Olsenw,Karl Heinz Rahnx, Josep Redony, Jose Rodicioz, Luis Ruilopea1,Roland E. Schmiedera2, Harry A.J. Struijker-Boudiera3, Pieter A. van Zwietena4,Margus Viigimaaa5 and Alberto Zanchettia6
Journal of Hypertension 2009, 27:000–000

Keywords: antihypertensive treatment, cardiovascular risk, guidelines,hypertension, organ damage

Abbreviations: ACE, angiotensin-converting enzyme; BP, blood pressure;DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate;ESC, European Society of Cardiology; ESH, European Society ofHypertension; ET, endothelin; IMT, carotid intima-media thickness; JNC,Joint National Committee; LVH, left ventricular hypertrophy; LVM, leftventricular mass; PDE-5, phosphodiesterase-5; PPAR-g, peroxisomeproliferators-activated receptor-g; PWV, pulse wave velocity; SBP, systolicblood pressure; WHO, World Health Organization

aClinica Medica, University of Milano-Bicocca, Ospedale San Gerardo, Milan,Italy, bPharmacology Department, Hopital Europeen Georges Pompidou,Paris, France, cDepartment of Medical and Surgical Sciences, Clinic ofInternal Medicine, University of Brescia, Brescia, dUniversity of Bologna,Clinica Medica, Bologna, Italy, eDivision of Nephrology and Hypertension,Centre Hospitalier Universitaire, Vaudois, Lausanne, Switzerland, fWilliamHarvey Research Institute, Barts and The London School of Medicine,Queen Mary University of London, London, UK, gDepartment of PreventiveCardiology, Institute of Clinical and Experimental Medicine, Prague, CzechRepublic, hDepartment of Cardiology and Angiology, University of Ghent,Ghent, Belgium, iHypertension Unit, Department of Internal Medicine, HospitalClinic, University of Barcelona, Barcelona, Spain, jBHF GlasgowCardiovascular Research Centre, University of Glasgow, Glasgow, UK,kIstanbul University Cerrhpa, School of Medicine, Istanbul, Turkey,lHypertension and Cardiovascular Rehabilitation Unit, Department ofCardiovascular Diseases, University of Leuven, Leuven, Belgium,mCardiometabolic Centre, St. Imre Hospital, Budapest, Hungary,nUniversity of Milano-Bicocca, Department of Clinical Medicine andPrevention, San Gerardo Hospital, Milan, Italy, oDepartment of Nephrology,Hannover Medical School, Hannover, Germany, pManchester Royal Infirmary,University of Manchester, Manchester, UK, qDepartment of Cardiology,Ullevaal University Hospital, Oslo, Norway, rCardiovascular Center Zuerich,Zuerich, Switzerland, sCardiologie et Hypertension Arterielle, CHU deGrenoble, Grenoble, France, tCardiology, Asklepeion General Hospital,Athens, Greece, uDepartment of Hypertension and Diabetology, MedicalUniversity of Gdansk, Gdansk, Poland, vDepartment of Clinical SciencesMedicine, University Hospistal, Malmoe, Sweden, wClinical Physiology andNuclear Medicine, Glostrup University Hospital, Glostrup, Denmark, xDivisionof Nephrology and Hypertension, Department of Medicine, University ofMunster, Munster, Germany, yInternal Medicine, Hospital Clinico, University ofValencia, Valencia, Spain, zDepartement of Medicine, University Complutense,a1Hospital 12 de Octubre, Madrid, Spain, a2Medizinische Klinik, UniversityErlangen-Nuernberg, Erlangen, Germany, a3Department of Pharmacology,University of Limburg in Maastricht, Maastricht, a4University of Amsterdam,Amsterdam, The Netherlands, a5Centre of Cardiology, North Estonia MedicalCentre, Tallinn, Estonia and a6University of Milan and Istituto AuxologicoItaliano, Milan, Italy

opyright © Lippincott Williams & Wilkins. Unauth

0263-6352 � 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

Correspondence to Professor Giuseppe Mancia, Clinica Medica, University ofMilan-Bicocca, San Gerardo Hospital, Via Pergolesi 33, 20052 Monza, Milan, ItalyTel: +39 039 2333357; fax: +39 039 322274; e-mail: [email protected]

Professor Stephane Laurent, Department of Pharmacology and INSERM U970,European Hospital Georges Pompidou, Paris Descartes University, 20 rue Leblanc75015 Paris, FranceTel: +33 1 56 09 39 91; fax: +33 1 56 09 39 92;e-mail: [email protected]

Received 16 September 2009 Accepted 16 September 2009

IntroductionIn the 2 years since the publication of the 2007 guidelines

for the management of arterial hypertension of the Euro-

pean Society of Hypertension (ESH) and the European

Society of Cardiology (ESC) [1], research on hyperten-

sion has actively been pursued and the results of new

important studies (including several large randomized

trials of antihypertensive therapy) have been published.

Some of these studies have reinforced the evidence on

which the recommendations of the 2007 ESH/ESC

guidelines were based. However, other studies have

widened the information available in 2007, modifying

some of the previous concepts, and suggesting that new

evidence-based recommendations could be appropriate.

The aim of this document of the ESH is to address a

number of studies on hypertension published in the last

2 years in order to assess their contribution to our expand-

ing knowledge of hypertension. Furthermore, some

critical appraisal of the current recommendations of the

ESH/ESC, as well as of other guidelines, might be a useful

step toward the preparation of a third version of the

European guidelines in the future.

The most important conclusions are summarized in

boxes. The points that will be discussed are reported

in Box 1.

orized reproduction of this article is prohibited.

DOI:10.1097/HJH.0b013e328333146d

mailto:[email protected]

mailto:[email protected]

http://dx.doi.org/10.1097/HJH.0b013e328333146d

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2 Journal of Hypertension 2009, Vol 27 No 00

Box 1. IssuesAssessment of subclinical organ damage for total cardiovascular risk stratification

(1) Heart

(2) Blood vessels

(3) Kidney

(4) Additional measures

(5) Subclinical organ damage as marker of a high cardiovascular risk

(6) Prognostic value of treatment induced organ damage changes

(7) Conclusion

Treatment approach

(1) When to initiate antihypertensive treatment

(2) BP goals

(3) Post hoc analysis of trials and effects on organ damage

(4) The J-curve phenomenon

(5) Are the 2007 recommendations still applicable?

Treatment strategies

(1) Choice of antihypertensive drugs

b-blockers

Thiazide diuretics

ACE inhibitors and angiotensin receptor antagonists

Calcium antagonists

New antihypertensive drugs

(2) Are ranking antihypertensive agents in order of choice useful or deceiving in practice?

(3) Preferred drugs

(4) Monotherapy and combination therapy

BP lowering with the two approaches

Two-drug combination as first step treatment

Preferred drug combinations

Fixed dose (or single pill) combinations

Conclusion

Therapeutic approach in special conditions

(1) Elderly

(2) Diabetes mellitus

(3) Renal disease

(4) Cerebrovascular disease

(5) Coronary heart disease and heart failure

(6) Atrial fibrillation

(7) Hypertension in women

(8) Erectile dysfunction

Treatment of associated risk factors

(1) Lipid lowering agents

(2) Antiplatelet therapy

(3) Glycemic control

(4) The issue of the polypill

New trials needed

Assessment of subclinical organ damage forstratification of total cardiovascular riskThe 2007 ESH/ESC guidelines recommend total cardio-

vascular risk be evaluated in each patient to decide about

important aspects of treatment: the blood pressure (BP)

threshold at which to commence drug administration, the

target BP to be reached by treatment, the use of two-drug

combinations as the initial treatment step, and the

possible addition to the antihypertensive treatment regi-

opyright © Lippincott Williams & Wilkins. Unautho

men of lipid-lowering and antiplatelet agents [1]. Among

the criteria to assess total cardiovascular risk, the Euro-

pean guidelines consider subclinical organ damage to be a

very important component, because asymptomatic altera-

tions of the cardiovascular system and the kidney are

crucial intermediate stages in the disease continuum that

links risk factors such as hypertension to cardiovascular

events and death. On the basis of a number of criteria

(prognostic importance, prevalence in the population,

rized reproduction of this article is prohibited.

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Reappraisal of guidelines on hypertension management Mancia et al. 3

availability and cost of the assessment procedures, etc.),

the 2007 European guidelines considered detection of

organ damage as important for the diagnostic and prog-

nostic evaluation of hypertensive patients. They further

subdivided the different types of organ damage into (1)

those that can be identified by relatively simple and cheap

procedures [electrocardiogram, serum creatinine, esti-

mated glomerular filtration rate (eGFR), and measure-

ment of urinary protein excretion in order to detect micro-

albuminuria or proteinuria], which were thus regarded as

suitable for routine search in the whole hypertensive

population, and (2) those that require more complex

procedures or instrumentations (echocardiogram, carotid

ultrasonography, pulse wave velocity), which were for this

reason only recommended for a more in-depth character-

ization of the hypertensive patient. Since then, other

studies have added useful information on the importance

of detecting subclinical organ damage in the hypertensive

population, strengthening the recommendation to use the

most easily available and the least costly procedures in the

routine examination of individuals with hypertension.

HeartA few recent papers have revived interest in the power of

the electrocardiogram to predict the risk of cardiovascular

events. In a prospective survey including 7495 American

adults, a new indicator of left ventricular hypertrophy

(LVH), the Novacode estimate of left ventricular mass

index that is based on both voltage and strain pattern

criteria, has been reported to be significantly related

to 10-year cardiovascular mortality [2]. The relation

remained significant after adjusting for age, SBP, smok-

ing, cholesterol, and diabetes. Furthermore, in the LIFE

trial, the investigators have reported that in hypertensive

patients with electrocardiographic LVH, left bundle

branch block identifies individuals at increased risk of

cardiovascular mortality (hazard ratio 1.6), sudden cardio-

vascular death (hazard ratio 3.5), and hospitalization for

heart failure (hazard ratio 1.7) [3]. Finally, a very recent

prospective study [4] focused on the R-wave voltage in

lead aVL as being rather closely associated with left

ventricular mass (LVM), and additionally predictive of

incident cardiovascular events even when hypertension

is not accompanied by electrocardiographic LVH (9%

higher risk for each 0.1 mV higher R-wave).

Additional evidence is also available on the predictive

power of cardiac abnormalities, as detected by echocardio-

graphy, an approach of continuing interest because of

its ability to more directly and precisely quantify LVM

and geometric LVH patterns. A retrospective study has

recently updated information from more than 35 000

normotensive and hypertensive participants with normal

left ventricular ejection fraction [5]. Despite normal left

ventricular function, an abnormal left ventricular geo-

metric pattern was found in 46% of the patients (35% left

ventricular concentric remodeling and 11% LVH), and the


associated risk of all-cause mortality was twice as large as

that of patients with normal left ventricular geometry.

Although in another study on an African–American popu-

lation, the relationship between left ventricular geometric

patterns and all-cause mortality was markedly attenuated

after adjusting for baseline variables, and remained signi-

ficant only in men [6], the increased risk associated

with LVH has been confirmed by other observations. In

a prospective study on a cohort of 1652 Greek hypertensive

patients followed up for 6 years, echocardiographic LVH

was significantly associated with either a composite of all-

cause mortality and cardiovascular events (hazard ratio

1.53) and with stroke (hazard ratio 2.01), after adjustment

for major cardiovascular risk factors [7]. Furthermore, a

retrospective analysis of 1447 Japanese hypertensive

patients who participated in the CASE-J trial showed that

cardiovascular events occurred about 2.6 times more fre-

quently in patients with a LVM index 125 g/m2 or more

compared with those with a LVM index below this value

[8]. Finally, in the PAMELA population, echocardio-

graphic LVH was associated with a four-fold to five-fold

significant increase in cardiovascular morbidity and

mortality when data were adjusted for a large number of

potential confounders, including office, home, and ambu-

latory BP values. A 10% increase in LVM increased the risk

more markedly when baseline LVM was already abnormal,

but an increasing risk was evident also when calculated

from LVM values within the normal range [9].

Blood vesselsThe relationship of carotid intima–media thickness (IMT)

and plaques with subsequent cardiovascular events,

already discussed in the 2007 guidelines, has been further

strengthened by data from ELSA [10], which have shown

that baseline carotid IMT predicts cardiovascular events

independent of BP (clinic and ambulatory) and this occurs

both for the IMT value at the carotid bifurcations and for

the IMT value at the level of the common carotid artery.

This suggests that both atherosclerosis (reflected by the

IMT value at the bifurcations) and vascular hypertrophy

(reflected by the common carotid IMT) exert an adverse

prognostic effect in addition to that of high BP. An adverse

prognostic significance of carotid plaques (hazard ratio 2.3)

has also been reported in a sample of residents of the

Copenhagen County free of overt cardiovascular disease,

which was prospectively followed for about 13 years [11].

Evidence has also accrued on the adverse prognostic value

of arterial stiffening. In the Copenhagen County popu-

lation, an increased pulse wave velocity (PWV >12 m/s)

was associated with a 50% increase in the risk of a cardio-

vascular event [11]. Furthermore, an independent predic-

tive value of PWV for cardiovascular events has been

shown in Japanese men followed for 8.2 years [12]. Finally,

indirect indices of aortic stiffness and wave reflection, such

as central BP and augmentation index, have been con-

firmed as independent predictors of cardiovascular events

in two recent studies [13,14]. In particular, in one of these


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studies of 1272 normotensive and untreated hypertensive

patients, only central SBP consistently and independently

predicted cardiovascular mortality after adjustment for

various cardiovascular risk factors, including LVM and

carotid IMT [14]. However, it should be emphasized

that in most available studies, the additive predictive

value of central BP beyond brachial pressure appears

limited, which leaves the question whether central BP

measurements should be regularly considered in the

clinical profiling of hypertensive patients in need of further

investigation.

KidneySeveral new data [15] reinforce the already solid evidence

on the prognostic value of eGFR that was available at the

time of the 2007 guidelines [1]. In the population of

Gubbio (Italy), an eGFR in the lowest decile was associ-

ated with a significantly higher incidence of cardiovas-

cular events (hazard ratio 2.14) [16], and in the above-

mentioned Greek study [7], an eGFR between 15 and

59 ml/min per 1.73 m2 was associated with a 66% increase

in the composite endpoint of all cause mortality and

cardiovascular events after adjustment for baseline

cardiovascular risk and independent of LVH [7]. Like-

wise, in a post hoc analysis of data from the VALUE trial

[17], eGFR according to the MDRD formula was signifi-

cantly predictive of all outcomes except stroke (with

hazard ratios between 1.23 and 1.70 according to the

different outcomes) and was more sensitive than calcu-

lation of the creatinine clearance value according to the

Cockroft–Gault formula, which was only predictive of

all-cause mortality.

The baseline eGFR by the MDRD formula turned out to

be importantly predictive of both renal and cardiovascu-

lar events also in the large number (n¼ 11 140) of type 2

diabetic patients included in the ADVANCE trial, even

when data were adjusted for many potential confounders,

including the concomitant urinary protein excretion

value. For every 50% reduction of baseline eGFR the

risk of cardiovascular events significantly increased

2.2-fold, the concomitant increase in the risk of cardio-

vascular death and renal events being 3.6-fold and

63.6-fold, respectively [18].

New evidence is also available to support the already

large amount of data in favor of the prognostic value of

the moderate increase in urinary protein excretion,

defined as microalbuminuria [19,20]. In two population

studies, the Gubbio study [16] and the Copenhagen

County study [11], microalbuminuria was confirmed as

an important predictor of cardiovascular outcome, the

adjusted hazard ratio being, respectively, 2.15-fold and

3.10-fold greater in patients with microalbuminuria

compared with those without. In the Gubbio study,

the association of microalbuminuria with low eGFR

had a multiplicative effect (hazard ratio 5.93). In the


ADVANCE trial [18], a change from one clinical stage

of albuminuria to the next was associated with a 1.6-fold,

2.0-fold, and 3.3-fold increase in the multivariate-

adjusted risk of cardiovascular events, cardiovascular

death, and renal events, respectively, this being the

case also when the change from normoalbuminuria to

microalbuminuria was involved. The effects of higher

baseline urinary protein excretion and reduced eGFR

were independent of each other and the association of

microalbuminuria and an eGFR value less than 60 ml/min

per 1.73 m2 brought about an additional increase in risk:

3.2-fold for cardiovascular events, 5.9-fold for cardiovas-

cular mortality, and 22.2-fold for renal events.

Additional measures of organ damageThe 2007 European guidelines mention a number of

additional measures of organ damage for which evidence

of prognostic relevance was available, but no use in the

clinical practice could be foreseen because of drawbacks

of practical relevance, such as the high cost and low

availability of the devices involved, the complexity and

time consumption inherent in the procedures, and in

several instances the lack of standardization of the values

obtained between laboratories and across countries.

Based on the evidence available in the last 2 years, no

addition to the measures of organ damage included in the

2007 guidelines can be supported, although the growing

availability of more sophisticated techniques and the

reduced cost of their use brought about by technological

progress, makes future additions likely.

In this context, the use of nuclear magnetic resonance

deserves special mention. Although not prospective in

nature, a very recent study systematically employing

nuclear magnetic resonance imaging in a group of 142

hypertensive patients without overt cardiovascular dis-

ease has provided the interesting information that silent

cerebrovascular lesions are even more prevalent (44%)

than cardiac (21%) and renal (26%) subclinical damage,

and do frequently occur in the absence of other signs

of organ damage [21]. Increasing evidence also relates

these lesions to cognitive dysfunction [22,23], a problem

of primary importance because of the senescence of

the population [24]. With magnetic resonance imaging

becoming more and more frequently employed in diag-

nostic procedures, silent cerebrovascular disease is likely

to become more frequently investigated in prognostic

and therapeutic studies in hypertension.

The prognostic value of structural alterations in small

subcutaneous arteries has recently been confirmed by

two independent studies [25,26]. However, the invasive

nature of this measurement prevents larger scale appli-

cation of this method. A new noninvasive method for

assessing the media–lumen ratio of small retinal arteries

seems promising for large-scale evaluation [27], although

its predictive value remains to be investigated.


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Evidence remains inconclusive on a marker of a vascular

alteration that has been actively investigated in the past

decade, namely endothelial dysfunction. In a population

sample of individuals without overt cardiovascular dis-

ease (67% with hypertension and 22% with diabetes

mellitus) from the Northern Manhattan study, measures

of flow-mediated vasodilatation predicted the incidence

of cardiovascular events, but this effect was not indepen-

dent of traditional cardiovascular risk factors [28]. Like-

wise, in the large cohort of elderly patients of the

Cardiovascular Health Study, flow-mediated vasodilata-

tion added very little to the prognostic accuracy of

traditional risk factors [29]. On the contrary, Muiesan

et al. [30] have recently reported that in a small cohort

(n¼ 172) of uncomplicated hypertensive persons fol-

lowed for about 8 years, flow-mediated vasodilatation

of the brachial artery below the median value was sig-

nificantly associated with a 2.7-fold increase in incident

cardiovascular events even after adjusting for all major

cardiovascular risk factors. However, the same group of

investigators also have reported that endothelial dysfunc-

tion in the subcutaneous vessels of hypertensive patients

was not predictive of cardiovascular events [31], possibly

because endothelial dysfunction in different vascular

beds may have a different prognostic significance.

Clearly, the prognostic value of endothelial dysfunction

in hypertension remains to be further elucidated.

It should be emphasized that the addition of new

measures of organ damage to the assessment of total

cardiovascular risk requires not only the demonstration

of their prognostic importance, but it has to improve the

power to predict the incidence of cardiovascular events.

This is by no means easy to be documented, and indeed

data are available that in some instances new risk factors

of individual prognostic significance do not improve,

when added to the others, the accuracy by which cardio-

vascular risk can be quantified, thus only making the

diagnostic procedures more complex, time consuming,

and costly. This is exemplified by the recent results of the

Framingham study, which showed that inclusion of

inflammatory markers did not lead to any substantial

improvement in the accuracy (sensitivity and specificity)

by which total cardiovascular risk was assessed [32].

Subclinical organ damage as a marker of highcardiovascular riskAlthough subclinical organ damage undoubtedly

increases the level of cardiovascular risk, the question

arises whether it always brings the patient into the high-

risk category, that is, an absolute risk of at least 20

cardiovascular events in 10 years per 100 patients. The

2007 European guidelines classify hypertensive patients

with subclinical organ damage among those with a high

total cardiovascular risk. This is further supported by

more recent evidence on the contribution of subclinical

cardiac, vascular, and renal damage to the total cardio-


vascular risk. As regards to subclinical cardiac damage,

analysis of the data provided by some of the major

prospective studies indicates that in hypertensive

patients, echocardiographic LVH, particularly if of the

concentric variety, is associated with an incidence of

cardiovascular events equal to or above 20% in 10 years

[5,7,33]. An incidence greater than 20% in 10 years has

also been reported for men, but not for women, with

echocardiographic LVH in the Framingham population

study [34]. Finally, in the hypertensive patients of the

CASE-J trial, echocardiographic LVH was associated

with a 10-year incidence of cardiovascular events of

24% compared with the 10% incidence seen in patients

without LVH [8].

Similar evidence exists for vascular damage. In the

elderly patients of the Cardiovascular Health Study

[35], the 10-year incidence of major cardiovascular events

was higher than 20% when the common carotid IMT

was 1.06 mm or more (fourth and fifth quintiles) and

below 10% in those with an IMT in the first quintile

(<0.87 mm). In the hypertensive patients of the ELSA

study [10], the incidence of all (major and minor) cardio-

vascular events was greater than 20% in 10 years when

IMT (common carotid plus bifurcation) was in the third

and fourth quartiles (�1.16 mm) or when at least one

plaque had been detected. In contrast, patients with IMT

in the first or the smallest IMT quartile (<0.98 mm) had

incident cardiovascular events below 10% in 10 years. In

hypertensive patients, the 10-year incidence of major

cardiovascular events was higher than 20% when caro-

tid-femoral PWV (aortic stiffness) was 16.3 m/s or more

(fifth quintile) and below 10% in those with an aortic

stiffness in the first and second quintiles [36]. Further-

more, even asymptomatic peripheral vascular disease as

detected by a positive ankle-brachial index has prospec-

tively been found to be associated in men with an

incidence of cardiovascular events approaching 20% in

10 years [37,38].

Finally, old and recent evidence leaves little doubt that

in hypertensive individuals, renal subclinical organ

damage is associated with a 10-year risk of cardiovascular

events of 20% or more. It has already been reported

some years ago that reduced renal function, defined by

a serum creatinine more than 1.5 mg/dl is associated with

a 10-year incidence of cardiovascular events 20% or more

[39,40]. In the recent prospective cohort of Greek hyper-

tensive patients [7], a low eGFR was associated with

incident cardiovascular events of about 20% in 10 years,

an even higher incidence being observed when low

eGFR occurred together with LVH. Furthermore, in

the hypertensive patients prospectively studied by

Jensen et al. [41], the incidence of ischemic heart disease

was 20% in 10 years in the presence of microalbuminuria

and of only 5% in its absence. Also, in the Gubbio

population study, the incidence of cardiovascular events


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was greater than 20% in 10 years, but only in those

individuals in whom microalbuminuria in the highest

decile was associated with eGFR in the lowest decile

[16]. Over 78% of these patients had hypertension.

The 2007 European guidelines classify patients with

subclinical organ damage as being at high risk also when

BP is in the high normal range, but admittedly evidence

that this is invariably the case is less clear. In the general

population of the Framingham study, no information was

made available on the prognostic value of echographic

LVH, separately in the normotensive and hypertensive

population [34]. Furthermore, in the same population,

the association of renal dysfunction with cardiovascular

events was lost after adjustment for cardiovascular risk

factors, including BP [42]. In the PREVEND population

study [43], microalbuminuria (20–200 mg/l) was associ-

ated with only a 4.7% cardiovascular mortality in 10 years,

that is, a moderate absolute risk according to the SCORE

classification [44], and in the nonhypertensive, nondia-

betic individuals of the Framingham study, a microalbu-

minuria above the median value was associated with a

rate of incident cardiovascular events of only 8.8% in

10 years compared with a 2.9% rate in individuals with

microalbuminuria below the median value [45].

Prognostic value of treatment-induced modifications ofsubclinical organ damageThe 2007 European guidelines have emphasized that

treatment-induced changes of organ damage affect the

incidence of cardiovascular events, thereby recommend-

ing that organ damage be measured also during treat-

ment. Reference was made to the data obtained in the

LIFE study [46], in which hypertensive patients in whom

treatment was accompanied by regression of echocardio-

graphic LVH or a delayed increase in LVM had less

incident cardiovascular events, including sudden death,

than those in whom no regression from or earlier pro-

gression to LVH occurred. It was also mentioned that

both in LIFE [47] and in other studies [48], a similar

relationship was found between treatment-induced

changes in proteinuria and renal or cardiovascular events.

This means that, compared with patients in whom treat-

ment had little or no antiproteinuric effect, reduction in

proteinuria was associated with a reduced incidence of

cardiovascular events and less progression to end-stage

renal disease.

Since 2007, data on the relationship between treatment-

induced changes in cardiac damage and cardiovascular

protection have been enriched by further analyses of the

LIFE study, which have shown that also treatment-

induced changes in left atrial dimension [49], left ven-

tricular geometry [50], and in electrocardiographic signs

of LVH correlate with incident cardiovascular event rate

[51]. Furthermore, there have been reports that in hyper-

tension, inappropriate changes in LVM during treatment


adversely affect cardiovascular prognosis [52]. Finally,

the predictive power of treatment-induced IMT changes

in the carotid arteries has for the first time been inves-

tigated in a recent analysis of ELSA trial data. This

analysis failed to show a predictive role of treatment-

dependent IMT changes, but the smallness of these

changes compared with the large individual differences

in baseline IMT makes it difficult to draw definitive

conclusions [10].

The correlation of treatment-induced changes in protei-

nuria with cardiovascular event incidence has been chal-

lenged by some findings of the ONTARGET trial. In this

trial on a large number of high or very high cardiovascular

risk patients, the group treated with a combination of an

angiotensin-converting enzyme (ACE) inhibitor and an

angiotensin receptor antagonist showed, throughout the

study duration, less increase in proteinuria than the group

on monotherapy with one or the other drug, but this

relative antiproteinuric effect was not accompanied by a

reduction in cardiovascular events and was even associ-

ated with an increase in renal events [53]. However, these

results do not necessarily undermine the important con-

cept that treatment-induced changes in proteinuria can

be a marker of the more or less pronounced beneficial

effects of treatment because alternative explanations for

the ONTARGET results are possible. For example, in

ONTARGET, most patients had a normal renal function

and few (4%) exhibited overt proteinuria, which resulted

in a very limited number of the endpoint that matters for

renal protection, that is, chronic renal failure. Further-

more, in the very high cardiovascular risk population

studied, the powerful blockade of the renin–angiotensin

system provided by the ACE inhibitor and angiotensin

receptor antagonist combination might have exhibited an

adverse effect of its own that superseded and masked

the beneficial influence associated with a reduction in

proteinuria. In favor of this beneficial influence are some

recent analyses of the ADVANCE study in patients with

type 2 diabetes. In these patients, on-treatment values of

proteinuria showed a close independent association with

both renal and cardiovascular events, the contribution of

proteinuria being unrelated to the concomitant values of

eGFR [18].

ConclusionEvidence on the important prognostic role of subclinical

organ damage continues to grow. In both hypertensive

patients and the general population, the presence of elec-

trocardiographic and echocardiographic LVH, a carotid

plaque or thickening, an increased arterial stiffness, a

reduced eGFR (assessed by the MDRD formula), or

microalbuminuria or proteinuria substantially increases

the total cardiovascular risk, usually moving hypertensive

patients into the high absolute risk range. The changes

in electrocardiographically or echocardiographically detec-

ted LVH induced by treatment reflect the effects on


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Box 2. Subclinical organ damage in total cardiovascular risk stratification

(1) In hypertension, assessment of total cardiovascular risk is important to optimize the decision about treatment

initiation, intensity and goals.

(2) Quantification of total cardiovascular risk must include a search for subclinical organ damage, which is

common in hypertension and has independent prognostic significance.

(3) In patients with hypertension, the presence of subclinical organ damage usually brings cardiovascular risk

into the high range. Subclinical organ damage alone may not be sufficient to bring normotensive individuals

into the high-risk category, although this may occur with multiple organ damage and the metabolic syndrome.

(4) As detailed in the 2007 ESH/ESC guidelines, several measures of renal, cardiac and vascular damage can be

considered for total cardiovascular risk quantification. Because of their simplicity, wide availability and limited

cost measures based on urinary protein excretion (including microalbuminuria), eGFR (MDRD formula), and

ECG are suitable for routine use. Cardiac and vascular ultrasounds are more and more easily available in

Europe, and their use in the evaluation of the hypertensive patient can be encouraged.

(5) Subclinical organ damage should be assessed both at screening and during treatment because a number of

treatment-induced changes in organ damage relate to cardiovascular and renal outcomes, thereby offering

information on whether the selected treatment is protecting patients from progressing organ damage and

potentially from cardiovascular events.

(6) Several other measures of subclinical organ damage have been shown to have prognostic significance, but

their complexity, low availability, and high cost prevent their routine clinical use. It is likely that technological

progress will make use of some of these measurements more common in the future. Any measure, however,

should be considered only if it adds to the overall precision of cardiovascular risk quantification.

cardiovascular events, thereby offering valuable infor-

mation on whether patients are more or less effectively

protected by the adopted treatment strategy. Despite

some recent inconsistent results [53], solid evidence

suggests that this is the case also for treatment-induced

changes in urinary protein excretion, although the problem

remains open for treatment-induced vascular changes.

Thus, assessing the presence of subclinical organ damage

is of crucial importance in the hypertensive population.

This assessment can make use of simple and cheap pro-

cedures that can provide routine information before and at

various times during treatment. It can also rely on more

sophisticated approaches that can further characterize

patients’ cardiac and vascular status. In all instances,

multiple organ damage assessment is useful because of

the evidence that in the presence of two signs of organ

damage (even when inherent to the same organ), cardio-

vascular risk may be more markedly increased, with an

almost inevitable upgrading to the high cardiovascular risk

category [7,16].

It is not clear from published data whether subclinical

organ damage can bring total cardiovascular risk to the

high range also in patients with high normal BP. However,

organ damage when it is particularly pronounced, or affects

multiple organs, or is accompanied by metabolic risk

factors, is associated with a two-fold or three-fold increase

in relative risk also in normotensive individuals [11,54–

56], and the 2007 guidelines recommend considering

relative risk as a guide for the need of treatment in

young and middle-aged patients. In this context, it is also

important to emphasize that the occurrence of undetected

organ damage in patients that doctors decide to treat

probably explains the apparently paradoxical findings of

several observational studies that the incidence of cardio-


vascular events is higher in treated than in untreated

hypertensive patients even after adjustment for usual

cardiovascular risk factors and past clinical history [57–

62]. This is consistent with the concept that antihyperten-

sive treatment even if beneficial cannot usually take a high

total risk back to a low-risk category [63]. These findings

presumably reflect the fact that in medical practice, BP-

lowering treatment is often deferred until organ damage

occurs, when complete reversibility is not achievable

[63,64]. More extensive use of organ damage assessment

may thus help to reach a more timely decision about the

initiation of treatment and thus favor its greater success.

Some of the issues discussed in Assessment of subclinical

organ damage for stratification of total cardiovascular risk

section are summarized in Box 2.

Treatment approachMajor guidelines [1,65–70] on the management of hy-

pertension recommend the initiation of antihypertensive

drugs in all patients with a SBP 140 mmHg or more and/or

a DBP 90 mmHg or more, and to adjust the treatment

strategy in order for the patients to be below these values.

They further recommend drug treatment to be initiated

within a lower BP range, that is, a SBP between 130 and

139 mmHg and a DBP between 85 and 89 mmHg in

patients with diabetes or a history of cardiovascular or

renal disease, aiming at achieving SBP/DBP values<130/

80 mmHg.

The 2007 ESH/ESC guidelines [1] have accompanied

these recommendations with information on the evi-

dence they are based upon, and a critical reappraisal of

this issue has recently been undertaken by members of

the present Task Force [71], in the light of further


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information provided by recent trials. The purpose of the

present ESH document is to clarify the size and the type

of evidence on which these recommendations are based,

and thus help the planning and conduction of future

studies which may fill possible evidence gaps.

When to initiate antihypertensive treatmentGuidelines recommend use of antihypertensive drugs in

patients with grade 1 hypertension at low or moderate

cardiovascular risk, that is, when BP is between 140 and

159 mmHg SBP and/or 90 and 99 mmHg DBP, provided

nonpharmacological treatment has proved unsuccessful.

However, it should be recognized that the evidence in

favor of this recommendation is scant because older trials

of ‘mild hypertension’ focused on patients whose BP

could be higher than those defining grade 1 hypertension

[72,73], or included high-risk patients [74]. Even the

recent FEVER trial [75], which was mentioned in the

2007 guidelines to support intervention in grade 1 hyper-

tensives with low/moderate cardiovascular risk, does not

provide conclusive evidence because mean entry BP was

just below 160 mmHg (159 mmHg), there was a large

proportion (89%) of patients receiving antihypertensive

therapy at baseline, and a noticeable number of patients

had evidence of organ damage or a history of cardiovas-

cular disease, thereby not belonging to the low-risk or

moderate-risk category [71].

Guidelines also point out that the BP threshold for drug

treatment is not related to age and recommend starting

antihypertensive drugs at SBP at least 140 mmHg or DBP

at least 90 mmHg in the elderly as well. However, as

shown in Table 1, there is no single trial on elderly

hypertensive patients [76–85] that recruited patients

with a SBP in the grade 1 hypertension range (i.e.,

<160 mmHg) [71]. Therefore, it can be concluded that

current guidelines recommendations on BP values at

which to initiate drug treatment in the elderly are not

based on results from trials, but derived from other


Table 1 SBP and DBP at randomization in antihypertensivetreatment trials in the elderly

Recruitment BP criteriaMean BP at

randomization

TrialSBP

(mmHg)DBP

(mmHg)SBP

(mmHg)DBP

(mmHg)

EWPHE 160–239 Or 90–119 183 101Coope/Warrender >170 Or >105 196 99SHEP �160 And <90 170 77STOP-1 �180 Or �105 195 94MRC-elderly 160–209 And <115 185 91Syst-Eur 160–219 And <95 174 85Syst-China 160–219 And <95 171 86SCOPEa 160–179 Or 90–99 166 90HYVET 160–179 And <110 173 91JATOS �160 And <120 171 89

BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure.Modified with permission from [71]. a In SCOPE, 50% of patients pretreated withlow-dose thiazide.

findings (see below) and perhaps encouraged by the

large benefits of antihypertensive therapy in all available

trials in the elderly, admittedly at higher initial blood

pressures.

Evidence is also scant for the guidelines recommendation

to initiate drug treatment in the high normal BP range

when patients have diabetes. Recommendations are sub-

stantially based on the results of the ‘normotensive’

component of the ABCD trial [86], which has important

limitations, however: ‘normotension’ was defined as a

SBP less than 160 mmHg, the trial size was small

(n¼ 480), the primary endpoint was the change in crea-

tinine clearance (with no statistically significant differ-

ence between treatments), and a statistically significant

reduction of cardiovascular events in the group random-

ized to more intensive treatment was limited to the

incidence of stroke but did not extend to other cardio-

vascular events. Recommendations also derive from sub-

group analyses of two large trials, MICROHOPE [87] and

ADVANCE [88]. However, in MICROHOPE, normo-

tension was defined by history, entry BP values were not

mentioned, and the statistical significance of cardiovas-

cular event reduction in the ‘normotensive group’ was not

reported; in ADVANCE, the benefit of antihypertensive

treatment was significant in patients with an entry SBP

140 mmHg or more, but not in those in whom it was

below this value. Similar findings were obtained when

stratification was based on the presence or absence of a

history of hypertension.

There have been strong recommendations to start anti-

hypertensive treatment at high normal BP values also in

patients with previous cerebrovascular disease. These

have been based on the report from the PROGRESS

trial [89] that in patients with a previous stroke or tran-

sient ischemic attack BP lowering was accompanied by a

marked reduction in the incidence of recurrent stroke and

cardiovascular events in both hypertensive and normo-

tensive patients. However, in this study, hypertension

was defined by SBP values of 160 mmHg or more, and in a

subsequent analysis, a significant reduction in recurrent

stroke with treatment was only observed when entry

SBP was 140 mmHg or more [90]. Furthermore, entry

BP values in PROGRESS were reported irrespective of

background treatment (present in 50% of the patients

[89,90]), and therefore they cannot be used to take

decisions on initiation of treatment in untreated patients.

Finally, the weight of evidence of PROGRESS has

not been helped by the substantially negative results

of a more recent large placebo-controlled trial of anti-

hypertensive treatment in patients with cerebrovascular

disease, the PROFESS study [91]. Although these nega-

tive results may be subject to various interpretations

[71,92], they remain a disturbing finding requiring

more straightforward investigation in a more simply

designed trial.


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As already discussed in the 2007 European guidelines [1]

and further analyzed in a recent review [71], although no

less than five trials are available [93–97], the information

whether drug treatment should be initiated at high

normal BP values in patients with coronary disease is

inconclusive. First, in most trials, attention was directed

to the putative-specific effects of the drugs studied rather

than to the BP-related ones, which were sometimes

incompletely quantified. Second, in these trials, patients

were subdivided for their higher or lower entry BP value

on a background of antihypertensive drug adminis-

tration, and thus the so-called ‘normotensive’ patients

probably belonged to a higher BP category when

untreated. Third, the results show considerable discre-

pancies between and even within trials [71].


Fig. 1

1

1

1

1

1

1

1

1

1

1

2S

‘Uncomplicated’ Hypertension

SBP (mmHg)

OS HDFP AUS MRC FEV

142

137

149

138

150

140

130

148

130

100

110

120

130

140

150

160

170

180

190

200

140

BP

Benefit

No benefit

Diabetes mellitusBP

Benefit

Partial benefit

No benefit

140143145

143

144

141

144

140137

128

138

132

162

153143

139

154

144

155

145

148

145

100

110

120

130

140

150

160

170

130

HOTSHEP

UKMHOPE

S.EurHT NT IR AM

RENPROG

ADVABCD IDNT

SBP (mmHg)

134134

10

11

12

13

14

15

16

17

146

Achieved SBP in patients randomized to a more active (filled rectangles) ohypertension (left upper panel), elderly hypertensive patients (right upper paprevious cardiovascular disease (CVD; right lower panel). The white part oSBP. The green, red and orange rectangles indicate, respectively, trials witbenefits, and trials with significant benefits of more active treatment limitedAbbreviations at the bottom of the rectangles indicate trials as follows: OS, OFEV, FEVER; EW, EWPHE; CW, Coope and Warrander; SHEP, SHEP; SSCOPE, SCOPE; HYVET, HYVET; JATOS, JATOS; HOT, HOT; UKPDS, Unormotensives); IDNT, IDNT (IR, irbesartan; AM, amlodipine); REN, RENAALPROF, PROFESS; PREV, PREVENT; HOPE, HOPE; EU, EUROPA; ACT, ACTR, TRANSCEND. For trial acronym see Acronym List section. Modified w

Blood pressure goalsThe evidence available on the BP targets of antihyper-

tensive treatment has recently been reviewed by some

members of this committee and is summarized in Fig. 1

[71]. As illustrated in the upper-left panel, in four out

of five trials in uncomplicated hypertensive patients

[72–75,98], SBP was reduced to less than 140 mmHg

in the actively treated group while remaining at or above

this value in the placebo or control group. In three out of

four trials, the BP difference was associated with a

difference in outcome, and in FEVER [75] this occurred

for on-treatment values that were just slightly below and

slightly above 140 mmHg. With the limitation men-

tioned in a previous section (that patients were not

invariably at low or moderate cardiovascular risk and


159

148

160

151

161

151

165

156

186

167

170

180

162

172

150

00

10

20

30

40

50

60

70

80

90

00

EWCW

SHEPSTOP

MRC-E S.Eur

S.Ch

SCOPEHYVET

Elderly

140

147

138

JATOS

BP (mmHg)

BP

Benefit

Partial benefit

No benefit

143

140

136132

129

130

124

130

124

136

130

133

128

138

130

122

140

136

150

150141

132

149

143

0

0

0

0

0

0

0

0

Previous cardiovascular disease

130

Stroke CHD

PATSPROG

ACCPROF PREV

HOPEEU

ACTAM EN

PEATR

CAM

SBP (mmHg) BP

Benefit

Partial benefit

No benefit

144145

135

r less active (open rectangles) treatment in trials on uncomplicatednel), patients with diabetes mellitus (left lower panel) and patients with

f the histogram indicates the between-group difference (D) in achievedh significant benefits of more active treatment, trials without significantto some secondary endpoints. CHD, coronary heart disease.SLO study; HDFP, HDFP-stratum I; AUS, Australian; MRC, MRC-mild;

TOP, STOP; MRC-e; MRC-elderly; S.Eur; Syst-Eur; S.Ch; Syst-China;KPDS; M.HOPE; MICROHOPE; ABCD, ABCD (HT, hypertensives; NT,; PROG, PROGRESS; ADV, ADVANCE; PATS, PATS; ACC, ACCESS;

TION; CAM, CAMELOT (AM, amlodipine; EN, enalapril); PEA, PEACE;ith permission from [71].

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with grade 1 hypertension), this evidence supports the

recommendation of guidelines to reduce SBP to less than

140 mmHg in the general population of patients with

grade 1 or 2 hypertension and low or moderate total

cardiovascular risk.

Whether this recommendation should also apply to

elderly hypertensive patients is unproved by outcome

trials, however. As shown in the upper-right panel of

Fig. 1, although in all trials [76–84], but one [85], the

groups of elderly hypertensive patients randomized to

more active treatment had a significantly lower incidence

of cardiovascular outcomes, in no trial (except the only

one with negative results [85]) the on-treatment SBP

values were lowered to less than 140 mmHg. Thus, there

is no trial evidence in support of the guidelines recom-

mendation to adopt the less than 140 mmHg SBP target

in elderly patients.

The lower panels of Fig. 1 show that the guidelines

recommendation to lower BP less than 130/80 mmHg

in patients with diabetes [86–88,99–106] or a history

of cardiovascular disease [89,91,93–97,107,108] is also

not supported by incontrovertible trial evidence. For

diabetes, the recommendation in favor of intense treat-

ment was probably due to the enthusiasm generated by

some trials, such as HOT [99] and Syst-Eur [102], show-

ing a greater absolute reduction of cardiovascular out-

comes for a small BP difference in diabetic patients than

in nondiabetic hypertensive patients. As shown in the

lower-left panel of Fig. 1, only in one small trial were SBP

values less than 130 mmHg actually achieved, and they

were associated with a doubtful reduction in cardiovas-

cular outcomes [86]. Similar results characterize trials in

patients with a history of cerebrovascular or coronary

disease with the additional confusing feature that in some

trials in which SBP was lowered to less than 130 mmHg,

no benefit was observed compared with the group with

higher on-treatment values (lower-right panel of Fig. 1).

Information derived from post hoc analysis of trials andtrials on organ damageInformation on BP thresholds and targets for drug treat-

ment has also been derived from post hoc analyses of

event-based trials and from studies on the effects of

treatment on organ damage of prognostic importance,

though, admittedly, this is weaker evidence.

Post hoc analyses of the incidence of cardiovascular events

in relation to the BP achieved by treatment have been

performed in the large group of hypertensive patients of

the HOT study [99], in the high cardiovascular risk

patients recruited for the VALUE trial [109,110], the

INVEST trial [111–114], and the ONTARGET trial

[115,116], and in the patients with diabetic nephropathy

of the IDNT trial [117,118]. In the HOT study, the

lowest incidence of cardiovascular events occurred at a


SBP of 138 mmHg and a DBP of 82 mmHg [99]. In

the VALUE trial, hypertensive patients in whom the

achieved BP was below 140/90 mmHg showed a clear-

cut reduction in the incidence of cardiovascular events

(stroke, myocardial infarction, and hospitalized heart fail-

ure) with respect to the patients in whom on-treatment

BP remained above these values, independent of the

type of treatment employed [109]. In the INVEST trial,

the incidence of cardiovascular events was progressively

smaller as the proportion of visits in which BP was found

to be controlled (<140/90 mmHg) increased even when

data were adjusted for patients’ demography, clinical

conditions, and treatments [112]. The greater cardiovas-

cular protection associated with on-treatment SBPs less

than 140/90 mmHg showed a trend for cardiovascular

events to become even less common as the achieved

SBP decreased to about 130 mmHg [113]. On the con-

trary, in the ONTARGET, clear-cut beneficial effects of

BP reductions were seen when initial SBPs were above

140 mmHg, even when adjustments for potential con-

founders were made, and at each initial BP, a greater BP

reduction was usually accompanied by a greater cardio-

vascular protection. However, in patients in whom initial

SBP was in the 130 mmHg range, the benefit was less

pronounced and mainly evident for stroke [115]. Similar

findings have recently been reported for the subgroup

of diabetic patients recruited in ONTARGET [116].

Finally, in the patients with diabetic nephropathy of

the IDNT reduction of SBP to less than 120 mmHg

was related to lower cardiovascular mortality [117] and

to progressive reduction of proteinuria as well as in end-

stage renal disease [118].

As to the relationship between BP and subclinical organ

damage, data from the LIFE trial have shown that the

frequency of LVH regression is linearly related to the BP

changes induced by treatment, the maximal efficacy

being found for large BP reductions from the entry

values [119]. A recently published study has also shown

that presence of ECG-LVH is reduced by tighter as

compared with less tight BP control (131.9/77.4 and

135.6/78.7 mmHg, respectively) in nondiabetic hyperten-

sive patients [120]. Furthermore, several studies have

provided evidence that antihypertensive treatment is

accompanied by a reduction or a delayed progression

in urinary protein excretion, be it in the proteinuric or

microalbuminuric range, even when initial BP is below

140/90 mmHg [121,122]. The most recent evidence has

been provided by the ADVANCE trial, which has shown

that in diabetic patients, most of them under antihyper-

tensive treatment, further BP lowering by the addition of

an ACE inhibitor–diuretic combination significantly and

markedly reduced the incidence of renal endpoints.

These mainly consisted of the appearance, the pro-

gression, or the regression of urinary protein excretion,

within a range of initial systolic or diastolic BP values

from above 160/100 to below 120/70 mmHg [123]. The


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hazard ratio for a renal endpoint was 0.81, 0.75, 0.85, and

0.70 in the actively treated as compared with the control

group, at initial SBP values equal or above 160, 159–140,

139–120, and less than 120 mmHg, respectively. Further-

more, this post hoc analysis of the ADVANCE data has

shown the adjusted risk of a renal endpoint to decrease

progressively as the SBP achieved during treatment

decreased to values of about 110 mmHg [123].

The J-curve phenomenonRecently, there has been some withdrawal from a perhaps

excessive enthusiasm for aggressive lowering of BP,

based on the data of some trials [91,108] as well as posthoc analyses of the results of other trials on high-risk

patients [113,115,124]. These data have raised the doubt

that in patients at high cardiovascular risk, antihyperten-

sive treatment regimens that reduce SBP to values close

or below 120–125 mmHg and DBP below 70–75 mmHg

may be accompanied by an increase (rather than a further

reduction) in the incidence of coronary events, that is, by

a J-curve phenomenon. This has led to readdressing the

question as to whether BP is sometimes lowered too far,

and in doing so, underperfusion of vital organs increases

cardiovascular risk. The issue is open to the following

considerations. First, although a BP value below which

organ perfusion is compromised must exist, observational

studies in patients initially free of cardiovascular disease

[125] show that the relationship between BP and cardio-

vascular event rate is substantially linear down to very low

BP values (about 110/70 mmHg), which are only excep-

tionally attained by antihypertensive treatment. Second,

it is possible that in high cardiovascular risk patients, an

impairment of the mechanisms that guarantee blood flow

autoregulation elevates the BP values below which organ

perfusion is reduced [92,126]. However, the extent of this

elevation (which may be different between patients in

relation to the degree of organ damage and age) has never

been unequivocally established by trials specifically

designed to explore the advantages of more versus less

intense BP lowering. Third, despite adjustment for

between-group initial demographics and clinical differ-

ences, post hoc analysis of trial results cannot escape the

problem that in the group in which on-treatment BP was

lowest, there could have been a greatest initial cardio-

vascular risk that caused both the excessive BP reduction

and the increased incidence of cardiovascular events.

Indeed, this is supported by the evidence of a similar

J-curve phenomenon in placebo-treated groups of several

trials [127]. Fourth, all these post hoc analyses consistently

showed that, the nadir of cardiovascular outcome inci-

dence was represented by a rather wide range of BP

values, that is between 120 and 140 mmHg SBP and 70–

80 mmHg DBP, suggesting that within this low BP range,

the differences in achieved cardiovascular protection are

small [71]. This is in line with the results of observational

studies that the relationship between BP and cardiovas-

cular events is linear when cardiovascular events are


quantified on a logarithmic scale [125], which implies

smaller absolute differences at lower BP values.

Are the 2007 recommendations still applicable?Although the trial evidence is scant, it appears reasonable

to reconfirm that, in grade 1 hypertensive patients at low

and moderate risk, drug therapy should be started, if BP

remains equal to or above 140/90 mmHg, after a suitable

time period with appropriate lifestyle changes with the

goal to bring BP below this cutoff value. Initiation of

antihypertensive treatment in grade 1 hypertension

(without waiting for BP to increase to grade 2 range or

organ damage to develop) is also suggested by a recent

analysis of all major trials with antihypertensive agents

[63]. This analysis has revealed that in trials on high

cardiovascular risk patients, the ‘residual risk’, that is, the

risk level attained by intense therapy (often including

lipid-lowering and antiplatelet agents), can very rarely

decrease below the cutoff defining a high-risk condition

(i.e., 20% cardiovascular events in 10 years). This means

that, although reduced by therapy, a high initial risk

remains high. On the contrary, in trials involving hyper-

tensive patients at initial low or moderate risk, the

‘residual risk’ could often be brought to less than 10%

in 10 years, which implies that earlier initiation of anti-

hypertensive therapy may be beneficial. These argu-

ments favor similar threshold and target BPs for drug

treatment in the elderly. With the current availability of

well tolerated drugs, BP lowering does not appear to be

associated with any substantial increase in adverse effects

or in cardiovascular or noncardiovascular risk.

Initiation of antihypertensive drug therapy in diabetic

patients with high normal BP is presently unsupported

by prospective trial evidence. This is the case also for the

lower BP goals (<130/80 mmHg) recommended for dia-

betics but never really achieved in any single large trial and

are even more rarely attained in medical practice. For the

time being, monitoring subclinical organ damage, and

particularly microalbuminuria and proteinuria, appears

to be the best guidance to decide the BP values for

treatment initiation as well as treatment goals in diabetic

patients. Perhaps, and at least until the completion of

studies such as ACCORD (in which the beneficial effects

of targeting BP below either 130 or 120 mmHg are pro-

spectively examined [128]), it may be useful to recom-

mend that in diabetes, SBP be reduced well below

140 mmHg, without mentioning specific targets that are

unproven. This would be in line with the results of the

ADVANCE trial in which the macrovascular and micro-

vascular benefits of antihypertensive treatment were seen

in diabetic patients in whom SBP was brought down to less

than 135 mmHg compared with patients on placebo in

whom SBP remained at approximately 140 mmHg [88].

Similar cautious recommendations can be given to patients

with previous cardiovascular events, for whom current trial

evidence is controversial concerning both initiation of


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Box 3. Treatment initiation

(1) Although trial evidence is scanty, it appears reasonable to recommend that, in grade 1 hypertensives (SBP

140–159 mmHg or DPB 90–99 mmHg) at low and moderate risk, drug therapy should be started after a

suitable period with lifestyle changes. Prompter initiation of treatment is advisable if grade 1 hypertension is

associated with a high level of risk, or if hypertension is grade 2 or 3.

(2) In patients with high normal BP (SBP 130–139 mmHg or DPB 85–89 mmHg) uncomplicated by diabetes or

previous cardiovascular events, no trial evidence is available of treatment benefits, except for a delayed onset

of hypertension (crossing the 140/90 mmHg cutoff).

(3) Initiation of antihypertensive drug therapy in diabetic patients with high normal BP is presently unsupported

by prospective trial evidence. For the time being, it appears prudent to recommend treatment initiation in high

normal BP diabetic patients if subclinical organ damage (particularly microalbuminuria or proteinuria)

is present.

(4) Trial evidence concerning antihypertensive drug treatment in patients with previous cardiovascular events in

absence of hypertension is controversial, and further trials must be completed before firm recommendations

can be given.

(5) In general, early BP-lowering treatment, before organ damage develops or becomes irreversible or cardio-

vascular events occur, appears a prudent recommendation, because in high-risk hypertensive patients, even

intense cardiovascular drug therapy, though beneficial, is nonetheless unable to lower total cardiovascular

risk below the high-risk threshold.

antihypertensive drug treatment when BP is in the high

normal range, and the benefit of aiming at a BP target of

less than 130/80 mmHg.

No prospective outcome trial has ever been performed in

those patients with a high normal BP that the 2007 ESH/

ESC guidelines [1] tentatively classified as being at high

cardiovascular risk because of the presence of multiple

risk factors, metabolic syndrome, or subclinical organ

damage. It has previously been mentioned that within

this BP range, subclinical organ damage may not invari-

ably lead to a high cardiovascular risk, and it is unclear

how often this may occur. The evidence in favor of BP-

lowering interventions in these patients is limited to that

reported by the TROPHY [129] and the PHARAO

studies [130], in which administration of an antihyper-

tensive drug delayed the onset of hypertension (i.e., the


Box 4. Blood pressure goals of treatment

(1) On the whole, there is sufficient evidence to recomm

below 90 mmHg) in all hypertensive patients, both tho

is only missing in the elderly hypertensive patients, in

never been tested in randomized trials.

(2) The recommendation of previous guidelines to aim at

in patients at very high cardiovascular risk (previo

consistently supported by trial evidence. In no rando

down to below 130 mmHg with proven benefits, and

patients with previous cardiovascular events have gi

(3) Despite their obvious limitations and a lower strength

progressive reduction of cardiovascular events incid

120 mmHg and DBP down to about 75 mmHg, althoug

small. A J-curve phenomenon is unlikely to occur unt

with advanced atherosclerotic artery diseases.

(4) On the basis of current data, it may be prudent to rec

130–139/80–85 mmHg, and possibly close to lower v

critical evidence from specific randomized trials is de

crossing of the 140/90 mmHg cut-off). Whether this goal

should be pursued mainly with lifestyle modifications or

with addition of antihypertensive agents remains

undetermined, however.

One last point deserves greater attention when making

recommendations for medical practice. For a number of

reasons (cost, progressively greater incidence of patient

dropout, long-term management difficulties) randomized

trials can only run for a few years and therefore extra-

polation of the results to the frequently much longer life

expectancy of patients is not without limitations. The

extrapolation may fail to take into account that the

benefit of antihypertensive treatment may become pro-

gressively more evident with time, possibly because

regression of organ damage has a slow time course, in

parallel with the long-term remodeling of large arteries,


end that SBP be lowered below 140 mmHg (and DBP

se at low moderate risk and those at high risk. Evidence

whom the benefit of lowering SBP below 140 mmHg has

a lower goal SBP (<130 mmHg) in diabetic patients and

us cardiovascular events) may be wise, but it is not

mized trial in diabetic patients has SBP been brought

trials in which SBP was lowered to below 130 mmHg in

ven controversial results.

of evidence, post hoc analyses of trial data indicate a

ence with progressive lowering of SBP down to about

h the additional benefit at low BP values becomes rather

il lower values are reached, except perhaps in patients

ommend lowering SBP/DBP to values within the range

alues in this range, in all hypertensive patients. More

sirable, however.

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Box 5. Choice of antihypertensive drugs

(1) Large-scale meta-analyses of available data confirm that major antihypertensive drug classes, that is,

diuretics, ACE inhibitors, calcium antagonists, angiotensin receptor antagonists, and b-blockers do not differ

significantly for their overall ability to reduce BP in hypertension.

(2) There is also no undisputable evidence that major drug classes differ in their ability to protect against overall

cardiovascular risk or cause-specific cardiovascular events, such as stroke and myocardial infarction. The 2007

ESH/ESC guidelines conclusion that diuretics, ACE inhibitors, calcium antagonists, angiotensin receptor

antagonists, and b-blockers can all be considered suitable for initiation of antihypertensive treatment, as well

as for its maintenance, can thus be confirmed.

(3) Because the percentage of patients responsive to any drug class is limited and patients responsive to one drug

are often not those responsive to another drug, keeping the number of drug options large increases the chance

of BP control in a larger fraction of hypertensives. This is of crucial importance because cardiovascular

protection by antihypertensive treatment substantially depends on BP lowering per se, regardless of how it

is obtained.

(4) Each drug class has contraindications as well favorable effects in specific clinical settings. The choice of

drug(s) should be made according to this evidence. The traditional ranking of drugs into first, second, third,

and subsequent choice, with an average patient as reference, has now little scientific and practical justification

and should be avoided.

(5) Drugs acting via direct renin inhibition are the only new classes of antihypertensive agents that have recently

become available for clinical use. Several additional new classes are under an early investigational phase.

Selective antagonism of endothelin receptors holds some promise to improve rate of BP control in hyper-

tensive patients resistant to multiple drug treatment.

small arteries, and cardiac structure associated with a BP

elevation [131]. This appears to be supported by the

results of the few trials in which patients were followed

for a number of years after termination of randomized

treatment. In the SYST-EUR and SHEP trials, for

example, the beneficial effects of antihypertensive treat-

ment on the incidence of cardiovascular events remained

evident years after termination of the double-blind phase

of the trial, despite the fact that antihypertensive treat-

ment was started also in the placebo group [132,133]. A

similar phenomenon, which is referred to as the ‘legacy

effect’, has also been reported for the Steno 2 trial [134],

which reported a postinterventional benefit on the micro-

vascular and macrovascular complications of type 2 dia-

betes after 13.3 years of follow-up with an intensive

multifactorial therapy that included antihypertensive

drugs and in the UKPDS trial [135] during a 10-year

follow-up of the effect of a previous 10-year intensive

blood glucose control in diabetes.

The most important points related to threshold and target

BP values for treatment are summarized in Boxes 3 and 4.

Treatment strategiesChoice of antihypertensive drugsIn their 2003 [136] and 2007 versions [1], the European

guidelines reviewed the large number of randomized

trials of antihypertensive therapy, both those comparing

active treatment versus placebo and those comparing

treatment regimens based on different compounds

(Box 5). They concluded that the main benefits of anti-

hypertensive treatment are due to lowering of BP per se,and are largely independent of the drugs employed.

Therefore, thiazide diuretics (as well as chlorthalidone


and indapamide), b-blockers, calcium antagonists, ACE

inhibitors, and angiotensin receptor antagonists can ade-

quately lower BP and significantly and importantly

reduce cardiovascular outcomes. All these drugs are suit-

able for the initiation and maintenance of antihyperten-

sive treatment either as monotherapy or in some combi-

nations with each other.

The issue of the equivalence of the various classes of

antihypertensive agents, and of various agents within a

given class, has been a long debated one, heralded in the

1970s by the incautious suspicion of a role played by

reserpine in breast cancer [137], and continuing in the

1990s with the campaign against calcium antagonists as

responsible for coronary events, bleeding, and cancer

[138,139]. After the acquittal of calcium antagonists, even

by their prosecutors, attention has been recently focused

by different groups of investigators on a possible infer-

iority of b-blockers and diuretics as well as on the possible

inferiority of ACE inhibitors for stroke prevention and of

angiotensin receptor antagonists for coronary disease

prevention. Obviously, paying careful attention to

possible adverse effects or limitations of both new and

old drugs is an obligation of physicians and clinical

epidemiologists and must be taken seriously by members

of guidelines committees. On the contrary, unfounded

suspicion should not be used to deprive patients of the

benefits of drugs.

b-Blockers

The evidence upon which b-blockers have been ques-

tioned as first choice antihypertensive drugs [140] and

actually downgraded in the British recommendations

[141] was discussed in the 2007 European guidelines.


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New arguments on the place of b-blockers in antihyper-

tensive therapy have been added since then [142–144].

In a meta-analysis of nine of 22 randomized controlled

trials of b-blockers [145], a significant inverse correlation

has been reported between the heart rate achieved by

b-blocker therapy and cardiovascular outcomes (i.e., the

lower the achieved heart rate, the higher the incidence of

outcomes), including myocardial infarction and heart

failure, known to be favorably influenced by b-blockade

[146,147]. On the contrary, a recent meta-analysis of 147

randomized trials (the largest meta-analysis so far avail-

able) reports only a slight inferiority of b-blockers in

preventing stroke (17% reduction rather than 29%

reduction with other agents), but a similar effect as other

agents on preventing coronary events and heart failure,

and a higher efficacy than other drugs in patients with a

recent coronary event [148]. Furthermore, the recent

publication of a 20-year follow-up of the UKPDS trial

[149] comparing atenolol and captopril in diabetes has

found the incidence of cardiovascular outcomes to be

similar in patients on the b-blocker or the ACE inhibitor,

with a reduction in all-cause mortality favoring the

b-blocker. This is consistent with retrospective obser-

vational data of large numbers of patients on different

antihypertensive treatment regimens for longer periods

than in randomized trials, showing that the incidence of

cardiovascular outcomes was not higher on atenolol-based

treatment than on other antihypertensive agents [150].

Finally, no systematic analysis has been made of the

possible role of a smaller BP reduction by b-blocker-

based treatment in those trials in which b-blockers

appeared to have a smaller effect on stroke. For instance,

interpolation of ASCOT data on stroke in the meta-

regression analysis of the Blood Pressure Lowering

Treatment Trialists’ Collaboration [151] makes it clear

that the odd ratio falls very close to the place expected

because of the 2.7 mmHg difference in SBP between

b-blocker/diuretic and calcium antagonist/ACE inhibitor

treatments [152]. On the whole, however, b-blockers do

not appear to be systematically inferior to other antihy-

pertensive agents in their ability to reduce BP. A recent

pooling analysis from more than 40 000 hypertensive

patients under different monotherapies has shown no

inferiority (and, possibly, a numerical superiority) of

b-blocker monotherapy [153] in lowering brachial BP.

However, studies like CAFE [154] suggest that, for the

same brachial SBP, central SBP may be higher with b-

blockers than with other antihypertensive agents because

of a greater wave reflection due to bradycardia and/or

peripheral vasoconstriction. This interesting observation

deserves to be confirmed, although its real impact on

antihypertensive management may be small because the

difference between peripheral and central BPs is known

to become attenuated at an older age [155,156], when

hypertension and antihypertensive treatment are most

common.


There is no doubt that b-blockers as well as diuretics

(especially when combined together) have adverse meta-

bolic effects and facilitate new-onset diabetes [157,158]

in predisposed patients such as those with the metabolic

syndrome or impaired glucose tolerance [55,159,160].

The importance of this phenomenon, however, may

have been exaggerated by the way results of most pro-

spective studies and trials have been analyzed; that is,

by limiting analyses of changes in plasma glucose or in

antidiabetic prescriptions to patients initially free of

diabetes or with a blood glucose below 7.0 mmol/l

(126 mg/dl). Indeed, a recent analysis of data from the

3.8-year long ELSA trial has shown that new diagnoses of

diabetes at the end of this study in patients without

diabetes at baseline are accompanied by a number of cases

in which diagnosis of diabetes at baseline was no longer

confirmed at the end of the study. However, the overall

balance remains positive for new-onset diabetes [160].

Furthermore, it is still unclear whether drug-induced

diabetes carries the same negative prognosis as naturally

occurring diabetes, with some authors emphasizing studies

showing that trial patients with new-onset diabetes do not

have a higher incidence of cardiovascular outcomes during

the trial and several years thereafter [133,161], whereas

others underline the opposite conclusions in other studies

[143,162–164].

It is also true that, when compared with other agents in

trials using subclinical organ damage as an endpoint,

b-blockers have been shown to be less powerful than

ACE inhibitors, angiotensin receptor antagonists, and

calcium antagonists in reducing an increased left ventri-

cular mass [165], carotid IMT thickening [166], aortic

stiffness [131], and increased small artery wall-to-lumen

ratio [167–169], and this may be supposed to result in less

cardiovascular protection in the long run. When discuss-

ing b-blockers, however, it should not be ignored that

they are not a homogeneous class, and that vasodilating

b-blockers, such as celiprolol, carvedilol, and nebivolol,

appear not to share some of the negative properties

described for other compounds. For instance, celiprolol

lowers aortic stiffness and central pulse pressure [170],

whereas atenolol does not [131]. Nebivolol, at doses

producing the same BP reduction, lowers heart rate

significantly less than atenolol [171], and because of

the lesser bradycardia combined with peripheral vasodi-

latation, it has better effects on central BP than atenolol

[172]. In the GEMINI study [173], carvedilol had less

adverse effects on glycosylated hemoglobin, total cho-

lesterol, and triglycerides than metoprolol; and nebivolol,

at variance from metoprolol, has been found to improve

insulin sensitivity [174] and to have the same metabolic

effects as an ACE inhibitor [175]. Both carvedilol and

nebivolol have been used in outcome trials in chronic

heart failure (admittedly not in hypertension) and

found capable of reducing the primary endpoint of

mortality and hospitalization [176]: in COMET, carvedilol


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treatment was accompanied by less new-onset diabetes

than metoprolol [177], and in the SENIORS trial, new-

onset diabetes had the same incidence on nebivolol or

placebo [178]. When compared with metoprolol, carvedilol

resulted in significantly less cases of microalbuminuria and

progression to proteinuria in hypertensive diabetic

patients [173], and nebivolol has recently been shown to

improve coronary flow reserve and left ventricular filling

pressure in the hypertensive heart [179]. Whether the

protective cardiovascular action shown by carvedilol and

nebivolol in patients with heart failure is also displayed in

hypertension remains to be determined in a controlled

trial.

Thiazide diuretics

A prominent role for thiazide-like diuretics in antihyper-

tensive therapy, such as that given to these compounds in

the JNC-7 report [66], is an object of continuing debate

[143,161]. The evidence that a BP lowering induced by

diuretics can reduce all types of cardiovascular events is

robust [161], but it cannot be denied that most of the

trials, the meta-analysis of which has been the basis for

raising doubts on b-blockers, have also used thiazides.

This makes it difficult to distinguish the separate role of

these two drug classes. Likewise, the diabetogenic role of

b-blockers and diuretics is difficult to discriminate, and

when it has been dissociated diuretics appear worse than

b-blockers [157]. Diuretics have rarely been studied in

depth for their capacity to regress organ damage, and

when tested have often been found inferior to calcium

antagonists or ACE inhibitors [165,180,181]. Further-

more, all large studies that have explored the tolerability

of various classes of antihypertensive agents on persist-

ence to therapy have found diuretics to be, together with

b-blockers, the least tolerated compounds [153] or those

accompanied by the least persistence on treatment

[182,183]. Finally, a recent meta-analysis has reported

outcome benefit for low-dose but not for high-dose

diuretics [184]. In addition, the results of the ACCOM-

PLISH trial (to be discussed in the preferred drug com-

binations section) have raised doubts as to whether

thiazides are always the best protective component of

combination therapy [185].

Angiotensin-converting enzyme inhibitors and angiotensin

receptor antagonists

The concept that ACE inhibitors may be somewhat

inferior to other antihypertensive agents in preventing

stroke has repeatedly been raised on the basis of some

meta-analyses [148,186] and meta-regression analyses

[187]. A pathophysiological hypothesis to support the

claim that ACE inhibitors may be inferior to angiotensin

receptor antagonists in preventing stroke has also been

elaborated [188]. On the contrary, it has been suggested

that angiotensin receptor antagonists would be inferior to

ACE inhibitors in preventing myocardial infarction

[189,190].


All these concepts, as well as their pathophysiological

interpretations, have been undermined by the results of

the very large ONTARGET, directly comparing cardio-

vascular outcomes under treatment with an ACE inhibi-

tor (ramipril) or an angiotensin receptor antagonist

(telmisartan) [191]. ONTARGET has shown telmisartan

not to be statistically inferior to ramipril as far as the

incidence of a composite endpoint including major

cardiac outcomes are concerned. A similar incidence of

strokes was also observed on both treatments. Recent

meta-analyses including older and more recent trials

confirm the conclusion that ACE inhibitors and angio-

tensin receptor antagonists have the same preventive

effect on myocardial infarction [192,193].

The absolute benefit induced by the relatively small BP

reduction produced by either treatment is more difficult to

calculate, because ONTARGET was deliberately con-

ducted in high-risk patients and for obvious ethical reasons

could not include a placebo comparison arm. Therefore, it

is difficult to decide whether the benefit has to be gauged

from historical comparison with the placebo arm of the

HOPE trial [93], carried out several years earlier, or with

the placebo arm of the simultaneously run TRANS-

CEND, on patients intolerant to ACE inhibitors [108].

The patients of TRANSCEND treated with placebo had a

slightly lower incidence of cardiovascular events than

placebo-treated patients in HOPE, either because higher

prevalence of concomitant therapies than in HOPE (but

similar to that in ONTARGET) or because of a higher

proportion of women.

ONTARGET [191] and TRANSCEND [108] have also

provided some additional information on the respective

role of an ACE inhibitor and an angiotensin receptor

antagonist on the appearance of new diabetes in high-risk

patients. Despite the fact that telmisartan has repeatedly

been shown to possess PPAR-g-activity [194], incidence

of new diabetes was nonsignificantly different between

telmisartan and ramipril in ONTARGET [191] and only

slightly and nonsignificantly lower incidences were

observed in TRANSCEND [108] and in PROFESS

[91] with respect to the placebo group. However, most

patients were also receiving other antihypertensive

agents that may have obscured the specific antidiabeto-

genic effects of the drugs being tested. Despite these

considerations, the claim that PPAR-g-activity may give

telmisartan a greater antidiabetogenic action remains

unproven.

Calcium antagonists

Calcium antagonists have been cleared from the suspi-

cion of causing a relative excess of coronary events by the

same authors who had raised the suspicion [195]. On the

contrary, some recent meta-analyses [148,186,187,196]

suggest that these agents may have some additional

advantage in preventing stroke, although it is not clear


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whether this can be ascribed to a specific protective effect

or to a slightly better BP control, often achieved in the

calcium-antagonist-treated patients. It is still unclear

whether calcium antagonists are less effective in protect-

ing against new-onset heart failure, as is apparent in

several studies and large meta-analyses [148,186]. The

recent meta-analysis by Law et al. [148], however, shows

that trials in which a BP difference was sought between

an antihypertensive agent and control, the efficacy of

calcium antagonists in preventing heart failure was only

slightly lower than that of other antihypertensive agents

(19 versus 24%). The question revolves around how much

of this apparent inferiority of calcium antagonists is a real

limitation in their cardiovascular protection, the result of

a difficulty in diagnosing a clinically relevant but soft

outcome such as an incipient heart failure, or a con-

sequence of trial designs preventing the use of diuretics

and ACE inhibitors (agents essential in heart failure

therapy) in patients randomized to calcium antagonists.

It is relevant that in trials in which a calcium antagonist

was always or commonly administered in combination

with a diuretic (FEVER [75]) or an ACE inhibitor

(ASCOT [197]), there was no statistically significant

excess of heart failure in the calcium antagonist arm.

Incipient heart failure has also been found to be markedly

reduced (�39%) in hypertensive patients on calcium

antagonist treatment compared with those on placebo

in the ACTION trial [96,198–200].

New antihypertensive drugs

The new drug that has substantially increased its data-

base in the last 2 years is aliskiren, a direct inhibitor of

renin at the site of its activation, which is now available

for treating patients both in United States and Europe.

The new data on aliskiren can be summarized as follows.

First, although the specific advantages of interfering with

the activation of renin are not yet clear [201,202], aliski-

ren has been shown to be effective in lowering SBP and

DBP in hypertensive patients when given in monother-

apy at a single daily dose. Second, the drug is effective

also in combination with a thiazide diuretic, a calcium

antagonist and an ACE inhibitor or an angiotensin recep-

tor antagonist [203–205]. Third, data have recently

emerged on the ability of aliskiren to protect against

subclinical organ damage when combined with an angio-

tensin receptor antagonist. In one study in diabetic

hypertensive patients with proteinuria, this drug combi-

nation led to a greater reduction in urinary protein

excretion than the administration of an angiotensin

receptor antagonist alone [206], but in another study

on hypertensive patients with LVH, the combination

did not cause a LVM reduction significantly greater than

that obtained by administration of an angiotensin recep-

tor antagonist alone [207]. In a third study in heart failure

patients, this combination was significantly superior to

angiotensin receptor antagonist administration in causing

a reduction in the plasma concentration of brain natriure-


tic peptide [208], a recognized prognostic marker for

heart failure [209]. It remains to be seen whether greater

effects on organ damage may also be obtained by increas-

ing the dose of traditional blockers of the renin–angio-

tensin system. The completion of ongoing hard end-

points trials with aliskiren in mono and combination

therapies is expected with interest. Meanwhile the avail-

able evidence justifies its use in hypertension, particu-

larly in combination with other agents. This is also

supported by the favorable tolerance profile of aliskiren.

The main side-effect appears to be an increased inci-

dence of diarrhea, but only at doses higher than the

recommended dose [203].

New antihypertensive agents that are currently under

investigation include nitric oxide donors, vasopressin

antagonists, neutral endopeptidase inhibitors, AT2

angiotensin receptor agonists, and antagonists of

endothelin receptors. Although their mechanisms of

action hold promise of BP-lowering effectiveness and

possibly of specific organ protection, their investigational

phase is still far away from use in the clinical setting,

and thus assessment of their pros and cons compared

with current drug options is impossible. An exception is

represented by endothelin receptor antagonists, because

a compound of this class that selectively blocks ETA

receptors, darusentan, has been recently tested in

patients defined as resistant, because of lack of BP

control on treatment with at least three drugs, including

a diuretic. Administration of darusentan on the top of the

existing treatment significantly reduced office and 24 h

mean BP over a 14-week period, with a doubling of the

percentage of patients achieving BP control and only a

moderate increase in the rate of side-effects (mainly

edema and sodium retention) compared with placebo

[210]. These results are potentially important because

resistant hypertension is not a phenomenon of marginal

proportion, the number of patients unable to achieve BP

control despite multiple drug treatment being around

15–20% [211].

Is ranking antihypertensive agents in order of choiceuseful or deceiving in practice?The 2007 European guidelines avoided ranking antihy-

pertensive agents in order of choice. Ranking started with

the first Joint National Committee report [212] and the

1978 WHO report [213], and was justified by the fact that

the few available agents widely differed in tolerability

and some of them could only be used in combination.

With the development of several well tolerated classes of

antihypertensive agents, the habit of ranking has con-

tinued for good reasons (such as the need to wait for the

evidence of benefit by new agents) but also for less good

reasons, such as the interest of pharmaceutical companies

in having their drugs classified as ‘first choice’, or the

pleasure of investigators to see their studies capable of

awarding ‘first rank’ to a drug [152].


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Box 6. Combination therapy

(1) Evidence has continued to grow that in the vast majority of hypertensive patients, effective BP control can only

be achieved by combination of at least two antihypertensive drugs.

(2) Addition of a drug from another class to the initially prescribed one should thus be regarded as a

recommendable treatment strategy, unless the initial drug needs to be withdrawn because of the appearance

of side-effects or the absence of any BP-lowering effect.

(3) The combination of two antihypertensive drugs may offer advantages also for treatment initiation, particularly

in patients at high cardiovascular risk in which early BP control may be desirable.

(4) Whenever possible, use of fixed dose (or single pill) combinations should be preferred, because simplification

of treatment carries advantages for compliance to treatment.

(5) As mentioned in the 2007 ESH/ESC guidelines, several two-drug combinations are suitable for clinical use.

However, trial evidence of outcome reduction has been obtained particularly for the combination of a diuretic

with an ACE inhibitor or an angiotensin receptor antagonist or a calcium antagonist, and in recent large-scale

trials for the ACE inhibitor/calcium antagonist combination. The angiotensin receptor antagonist/calcium

antagonist combination also appears to be rational and effective. These combinations can thus be recom-

mended for priority use.

(6) Despite trial evidence of outcome reduction, the b-blocker/diuretic combination favors the development of

diabetes and should thus be avoided, unless required for other reasons, in predisposed patients. Use of an

ACE inhibitor–angiotensin receptor antagonist combination presents a dubious potentiation of benefits with a

consistent increase of serious side-effects. Specific benefits in nephropathic patients with proteinuria

(because of a superior antiproteinuric effect) expect confirmation in event-based trials.

(7) In no less than 15–20% of hypertensive patients, BP control cannot be achieved by a two-drug combination.

When three drugs are required, the most rational combination appears to be a blocker of the renin–

angiotensin system, a calcium antagonist, and a diuretic at effective doses.

However, once it is agreed that (1) the major mechanism

of the benefits of antihypertensive therapy is BP lowering

per se, (2) the effects on cause-specific outcomes of the

various agents are similar or differ by a minor degree,

(3) the type of outcome to occur in a given patient is

unpredictable, and (4) all classes of antihypertensive

agents have their pros and cons (well summarized in

Tables 7 and 8 of the 2007 ESH/ESC guidelines), it is

obvious that any all-purpose ranking of drugs for general

antihypertensive usage is unnecessary and probably

deceiving [152]. It is on the basis of this striving for

ranking that at different times investigators have been

warning the media that millions of people may be dying

every year because of the use of calcium antagonists, the

use of b-blockers, or the use of angiotensin receptor

antagonists. These campaigns cause lay people to wonder

whether antihypertensive therapy is beneficial or danger-

ous. This behavior should be discouraged. Even reasons

based on costs, often used to justify ranking, have

recently been weakened by the advent of generic com-

pounds within every class of antihypertensive agents.

The 2007 European guidelines [1], rather than indulging

in an all-purpose ranking, decided to prepare a table with

drugs to be preferred in specific conditions, on the basis of

the concept that different classes and sometimes differ-

ent agents within the same class have some properties

that can make them more or less suitable in given

conditions. This fits well the general purpose of Euro-

pean guidelines, that of being ‘educational and not pre-

scriptive or coercive for the management of individual

patients who may differ widely in their personal, medical,


and cultural characteristics’ [1], thus requiring decisions

different from the average ones recommended in several

other guidelines.

Preferred drugsBox 11 in the 2007 European guidelines [1] is the core for

the ranking of agents for specific conditions rather than

for general usage. No single agent is generally proscribed,

but each agent can be preferentially prescribed in specific

conditions [152]. Only minor differences from what indi-

cated in 2007 should be considered now, as discussed in

specific sections below.

Monotherapy and combination therapyBlood pressure lowering with the two approaches

The 2007 ESH/ESC guidelines underline that, no matter

which drug is employed, monotherapy can effectively

reduce BP in only a limited number of hypertensive

patients, most of whom require the combination of at

least two drugs to achieve BP control [1] (Box 6). A recent

meta-analysis of 42 studies has shown that combining two

agents from any two classes of antihypertensive drugs

increases the BP reduction much more than doubling the

dose of one agent [153]. Admittedly, the advantage of

combination therapy over monotherapy may partly be

due to the fact that any agent used in monotherapy is

ineffective or scarcely effective in a number of patients,

so that its combination with an agent effective in these

patients must induce a greater response than doubling

the dose of an ineffective agent. However, although it is

possible that the use of two drugs together implies the

administration of a futile one, searching for the most


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effective monotherapy in every given patient is painstak-

ing, and may discourage compliance (although pharma-

cogenetics may in future provide predictive clues).

Furthermore, there are physiological and pharmacologi-

cal synergies that justify the greater effectiveness of drug

combinations, and this strategy appears to be that on

which the selection of antihypertensive medication may

be increasingly based. In a public health perspective, it

seems desirable to foresee a substantial increase in the

use of combination treatment in clinical practice from the

relatively low prevalence of today [214]. This could help

attain the goal of substantially improving BP control in

the hypertensive population from its present low rate

worldwide [215].

Two-drug combinations as first step treatment

The 2007 ESH/ESC guidelines [1] recommend the com-

bination of two drugs to be considered as initial treatment

whenever hypertensive patients have a high initial BP or

are classified as being at high/very high cardiovascular risk

because of the presence of organ damage, diabetes, renal

disease, or a history of cardiovascular disease. This recom-

mendation was not based on evidence from morbidity/

mortality trials because in no study has the advantage of

this approach been prospectively assessed. It was based on

the arguments that (1) combination therapy can reduce BP

to a greater extent and achieve the BP goal more promptly,

(2) when a high-risk condition exists, an event may occur

within a relatively short time interval, requiring protective

interventions to be implemented without an excessive

delay, (3) in several trials, the protective effect of BP

reduction became manifest shortly after initiation of the

BP-lowering treatment, and (4) initial combination treat-

ment may be associated with a lower degree of treatment

discontinuation, possibly because treatment discontinu-

ation (an extremely common phenomenon [182,183,216])

depends also on the frustration that originates from the

patient’s perception of the inability to reach BP control

[217]. In a post hoc analysis of the VALUE trial [109],

the cardiovascular event rate was less regardless of the

type of treatment in patients in whom BP control

(<140/90 mmHg) was achieved within 1 month. Although

suggestive, the VALUE data obviously do not provide

indisputable evidence for the advantage of early BP con-

trol (and thus initiation of treatment with a two-drug

combination), as it is possible, and even likely, that the

immediate responders might have been at lower cardio-

vascular risk, which could also be the reason for the more

prompt BP reduction obtained with treatment. In order to

validate combination therapy as a first step strategy at least

in high-risk hypertensive patients, an appropriate trial

could be conducted comparing earlier BP control by a

combination of two drugs to later control achieved by

initial monotherapy followed by the two-drug combination

in those patients requiring it. However, it appears doubtful

that the issue really deserves trial evidence, and probably

the choice between initiating with monotherapy or com-


bination may better be based on the wisdom of the

previously mentioned arguments.

Preferred drug combinations

Some of the large-scale trials published in the last 2 years

importantly expanded information on the advantages and

disadvantages of several two-drug combinations in hyper-

tension. The new evidence available and its implications

for guidelines recommendations are discussed below.

Angiotensin-converting enzyme inhibitor–diuretic com-binations The combination of an ACE inhibitor, perin-

dopril, and the diuretic indapamide had already been

shown in the PROGRESS study to have a greater BP-

lowering effect than the ACE inhibitor alone and, in

parallel, a much greater preventive effect on recurrent

stroke [89]. In ADVANCE [88], the same combination of

indapamide and perindopril given to patients with type 2

diabetes (on top of continuation of preexisting therapy)

for more than 4 years was followed by a significantly

greater antihypertensive effect than administration of

placebo (SBP and DBP difference �5.6 and �2.2 mmHg,

respectively). This was associated with a reduced inci-

dence (�9%) of diabetes-related complications (composite

endpoint of macrovascular and microvascular outcomes).

In addition, the perindopril–indapamide combination was

well tolerated with an overall rate of adverse effects only

slightly greater than that observed in the placebo group,

and a high number of patients (>80%) remaining on active

drug treatment throughout the trial. Similarly, in the large

majority of the very elderly patient HYVET [84], the

administration of the indapamide–perindopril combi-

nation resulted in a greater BP reduction as well as a lower

rate of cardiovascular outcomes and serious side-effects

compared with placebo.

Angiotensin-converting enzyme inhibitor–calcium an-tagonist combinations A combination of an ACE inhibi-

tor and a dihydropyridine calcium antagonist was the most

widely used combination therapy in Syst-Eur and Syst-

China [81,82], as well as in the HOT study [99] in order to

achieve lower BP goals. INVEST used the combination of

a nondihydropyridine calcium antagonist, verapamil, and

the ACE inhibitor trandolapril with comparable beneficial

effects as the combination of a b-blocker and a diuretic

[111]. The combination amlodipine–perindopril was

widely used in the ASCOT study, being more effective

in lowering BP and cardiovascular events than the com-

bination of a b-blocker with a thiazide [197].

In the ACCOMPLISH trial [185], more than 11 000

hypertensive patients with a relatively elevated cardio-

vascular risk were randomized, after stopping previous

treatment, to receive an ACE inhibitor, benazepril, plus

either the calcium antagonist amlodipine or hydrochlor-

othiazide. Over the 3 years of follow-up, both treatments


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reduced BP very effectively, the average on-treatment

values being 132.5/74.4 mmHg in the hydrochlorothia-

zide group and about 1 mmHg lower (131.6/73.3 mmHg)

in the calcium antagonist group. The rate of serious side-

effects was limited and similar between the two groups.

In the group receiving the benazepril–amlodipine com-

bination, however, the incidence of the primary endpoint

(a composite of several cardiovascular fatal and nonfatal

events) was 20% less than in the group receiving

the benazepril–hydrochlorothiazide combination, with

a significant reduction also in cause-specific events such

as myocardial infarction, although not heart failure. This

provides outcome evidence in favor of the concomitant

administration of an ACE inhibitor and a calcium

antagonist that was hitherto unavailable. However, it

would be premature to conclude from this trial that an

ACE inhibitor–calcium antagonist combination is inher-

ently and invariably superior to the combination of an

ACE inhibitor and a diuretic. In ACCOMPLISH, the rate

of cardiovascular outcomes was lower than expected

in high-risk patients, possibly because of the extensive

use of statins (68%), antiplatelet agents (65%), and

revascularization procedures (18–20%). The ACCOM-

PLISH findings may also depend on the large proportion

of diabetic patients included (60%): indeed, in the STAR

study [218], hypertensive patients with an impaired

fasting glucose exhibited a worse metabolic response

to the glucose load test (as well as a greater rate of

new-onset diabetes) if treated with a combination of a

blocker of the renin–angiotensin system and a diuretic

than if treated with the combination of a renin–angio-

tensin system blocker and a calcium antagonist.

Combination of an angiotensin receptor antagonist witha calcium antagonist or a diuretic An angiotensin recep-

tor antagonist has been frequently combined with a

diuretic in a number of trials, such as LIFE [219] and

SCOPE [83,220], which have documented the protective

effects of this treatment strategy. Until now, no outcome

study has been conducted using the combination of an

angiotensin receptor antagonist with a calcium antagon-

ist. An exception is the RENAAL trial, in which the

benefit of losartan (versus placebo) in delaying pro-

gression to end-stage renal disease was seen on the top

of preexisting antihypertensive therapy frequently

including calcium antagonists [105]. Furthermore, a large

body of evidence exists that combining an angiotensin

receptor antagonist with a calcium antagonist or a diuretic

provides an effective reduction of BP and a high rate of

BP control in a variety of hypertension categories, has a

tolerability profile even more favorable than that seen

when an ACE inhibitor is used instead (because cough

and angioedema are much less frequently seen) and

protects against subclinical organ damage [221–223].

Evidence has grown in particular on the combination

of an angiotensin receptor antagonist with a calcium

antagonist (usually amlodipine), which has been proved


capable of most effectively reducing even severe hyper-

tension [223,224].

Combinations of calcium antagonists with diuretics orb-blockers Despite the fact that small pharmacologic

studies have raised doubts on the synergistic effects of

adding a diuretic to a calcium antagonist, this combi-

nation was included in the recent meta-analysis by Wald

et al. [153] without detracting from the demonstration

of a greater BP-lowering effect of combining calcium

antagonists with other drugs compared with doubling the

calcium antagonist dose in monotherapy. Even more

importantly, the association of a calcium antagonist with

a diuretic has been used in the FEVER, ELSA, and

VALUE trials [75,166,225] in the treatment arms associ-

ated with greater benefits. No outcome trial has explored

the combination of a calcium antagonist with a b-blocker,

but this has been the second used association in the HOT

study [99].

Angiotensin-converting enzyme inhibitor–angiotensinreceptor antagonist combinations The 2007 ESH/

ESC guidelines [1] did not regard the combination of

an ACE inhibitor and an angiotensin receptor antagonist

among those best suited for widespread use because they

act, though at a different level, on the same BP control

mechanism, that is, the renin–angiotensin system. The

2007 European guidelines, however, reported some

results in chronic kidney disease or diabetic patients

[226], mostly with proteinuria, claiming a greater anti-

proteinuric effect than with administration of an ACE

inhibitor or an angiotensin receptor antagonist alone. The

widespread use of this combination has now been ques-

tioned by the results of ONTARGET [53,191], in which

the combination of full doses of telmisartan and ramipril

reduced the initial BP values slightly more than the

reduction seen with the administration of one or the

other drug alone, without, however, any further reduction

in cardiovascular or renal endpoints (except proteinuria),

and indeed with a greater number of renal side effects

and a more frequent discontinuation of the initial treat-

ment. As mentioned in a previous section, a post hocanalysis of the BP changes in ONTARGET [115] has

elaborated the hypothesis that excessive lowering of BP

in patients whose baseline BP was less than 130 mmHg

(either spontaneously or as effect of previous therapy)

may have been responsible for an excess rather than

a reduction of cardiovascular events. An alternative

explanation that has been advanced [63] is that in

ONTARGET, the multiple therapies used had already

brought these high-risk patients to the bottom level of

cardiovascular risk achievable, and that combination of

the full doses of two blockers of the renin–angiotensin

system could not further reduce the risk. However, the

adverse effects of the administered drugs were free to

manifest themselves. Furthermore, the reasons have been

discussed that make it difficult to extrapolate the


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ONTARGET findings to the general population of

hypertensive patients.

Nonetheless, the results of ONTARGET do not support

large-scale use of this combination of drugs in hyperten-

sion and suggest that its use in proteinuric renal patients

should be studied further and more critically. A recent

meta-analysis of 49 studies, albeit small and mostly short

term, has confirmed that the combination of the two

blockers of the renin–angiotensin system has signifi-

cantly greater antiproteinuric effect than either com-

ponent [227]. However, although reduction of proteinuria

is often considered to lead to and/or reflect renoprotection

(i.e., delayed occurrence of end-stage renal disease) [228],

proteinuria reduction, particularly in short-term studies,

should not be taken as necessarily equivalent to renal

function preservation and prevention of cardiovascular

outcomes. An example of this are some findings of the

ONTARGET study [53] already discussed.

In this context, it should be remembered that the results

of the only study (the COOPERATE study) that

reported a superior protective effect of double blockade

of the renin–angiotensin system on renal outcomes [229]

have been questioned [230,231]. Also, the widely quoted

favorable results of concomitant ACE inhibitor and angio-

tensin receptor antagonist administration reported in

trials on patients with left ventricular dysfunction or heart

failure should be considered cautiously, as the benefits

were not seen in all trials (absent in VALIANT [232]),

or they were small (Val-HeFT [233]) or evident only if

hospitalization was added to mortality (CHARM [234]).

Finally, in all these trials, the combination markedly

increased the incidence of side-effects such as hyperka-

lemia and an elevation in serum creatinine.

Fixed dose (or single pill) combinations

Guidelines have long favored the use of combination of

two antihypertensive drugs at fixed doses in a single tablet,

because reducing the number of pills that have to be taken

daily has been shown to improve compliance [235], which

is low in hypertension. Use of fixed dose combinations of

two drugs can directly follow initial monotherapy when

addition of a second drug is required to control BP, or be

the first treatment step when a high cardiovascular risk

makes early BP control desirable. This approach is now

facilitated by the availability of different fixed dose com-

binations of the same two drugs, which minimizes one of its

inconveniences, that is, the inability to only increase the

dose of one drug but not that of the other.

Conclusion

New and old evidence strongly supports combination

treatment as the most effective strategy to control BP,

and therefore recommends treatment strategies largely

based on the addition of a drug from another class to the

initially prescribed agent, whenever BP control is not


achieved, unless the starting drug needs to be changed

because of side-effects or the absence of any BP

reduction. It suggests that the combination of two anti-

hypertensive drugs may offer advantages also as first step

treatment, particularly in patients at high cardiovascular

risk, in whom early BP control may be desirable. It favors,

whenever possible, the use of fixed dose combinations of

two drugs in a single tablet because of the advantage

brought about by simplification of the treatment regimen.

Finally, it warns against the use of a combination of an

ACE inhibitor and an angiotensin receptor antagonist at

least in very high cardiovascular risk patients such as

those in ONTARGET. It remains to be established

whether the latter combination may have a beneficial

role in patients with chronic renal disease and proteinuria,

or even in some lower risk hypertensives.

Because the 2007 European guidelines did not include

the ACE inhibitor–angiotensin receptor antagonist

combination between the preferred combinations, the

scheme they presented does not appear to require sub-

stantial modification at present. It should be underlined,

however, that outcome reduction has been documented

in trials using the following combinations: ACE inhibitor

and diuretic, angiotensin receptor antagonist and diure-

tic, calcium antagonist and diuretic, and ACE inhibitor

and calcium antagonist. Successful trials have also used

b-blocker and diuretic in association, but this is the

combination more easily inducing new diabetes in pre-

disposed patients [158].

Finally, it is important to remember that no less than 15–

20% of the patients need more than two antihypertensive

drugs to achieve an effective BP reduction. The combi-

nation of a blocker of the renin–angiotensin system, a

calcium antagonist and a thiazide diuretic may be a rational

three-drug combination, although other drugs, such as a

b-blocker or an a-blocker, may be included in a multiple

approach, depending on the clinical circumstances.

Therapeutic approach in special conditionsElderlyBoth the 2003 [136] and 2007 ESH/ESC guidelines [1]

regretted that, although there was overwhelming evi-

dence of the benefits (outcome reduction) of pharmaco-

logical lowering of BP in the elderly, this evidence was

inconclusive for patients aged 80 years or above, in whom

only a meta-analysis of a limited number of patients from

various trials [236] and the pilot HYVET [237] were

available, suggesting beneficial effects for morbidity

but not for mortality.

Now this gap in the evidence has been filled with the

much expected publication of the results of the HYVET

[84]. In HYVET, 3845 patients aged 80 years or more

in whom entry SBP was 160 mmHg or more (average

173 mmHg) were randomized to receive either placebo or


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active treatment, consisting of indapamide (1.5 mg daily)

and the eventual addition of the ACE inhibitor perindo-

pril (2 and 4 mg daily) with the target to attain a SBP value

below 150 mmHg. Drug administration (with the inda-

pamide–perindopril combination given in about three-

quarters of the patients) reduced BP to a value much

lower than placebo, that is, 144/78 versus 161/84 mmHg.

This was accompanied by clear-cut beneficial effects,

and, according to advice from the safety board, the trial

was stopped after an average treatment duration of less

than 2 years. The beneficial effects consisted of a 30%

reduction in stroke (just short of statistical significance)

and statistically significant reductions in congestive heart

failure (64%), major cardiovascular events, and all-cause

death (21%). These results indicate that even in the very

elderly stratum of the population, antihypertensive treat-

ment does not only prevent cardiovascular morbid events

but also translates into prolongation of life.

On the basis of the important evidence provided by

HYVET [84], guidelines can now more positively re-

commend that antihypertensive treatment be extended

to hypertensive patients aged 80 years and above. How-

ever, in consideration of the very old age of the patients

to which recommendations are directed, the character-

istics of the population included in HYVET and the

nature of the study should be given some attention, in

order not to extend treatment recommendations to indi-

viduals or contexts different from those of HYVET.

HYVET deliberately recruited patients without cardio-

vascular disease, and in good physical and mental con-

ditions, and excluded ill and frail individuals who are so

frequent among octogenarians. Although alterations of

baroceptor control often occur in the very elderly [238],

HYVET patients had similar BP values in the sitting and

standing positions even on treatment, confirming the

interpretation that particularly healthy individuals were

enrolled. The report that incidence of adverse effects

was lower in the active treatment arm than in the placebo

arm, underlines the excellent tolerability of drugs used

and the fact that the adverse effects were more likely

to be due to the hypertension per se than to the treat-

ment. Nonetheless, this supports once more the highly

selected nature of the octogenarians enrolled. Finally,

the premature interruption of the trial made its duration

so short (1.8 years) as to leave unanswered the question

whether the benefit of antihypertensive treatment

persists for several years.

In conclusion, an evidence-based general recommen-

dation can now be given to prescribe antihypertensive

treatment to octogenarians with SBP above 160 mmHg

with the target to lower it below 150 mmHg, but because

of differences in the general health of very elderly

patients, the decision to treat should be taken on an

individual basis, and BP lowering should be in any case

gradual and carefully monitored by the doctor.


Since the publication of the 2007 ESH-ESC guidelines,

some additional useful information on the treatment of

hypertension in the elderly has been added. A large

prospective meta-analysis of major antihypertensive

therapy trials has been published, showing that patients

aged less or more than 65 years achieve the same pro-

portional benefit from a given lowering of BP and there is

no hint that different classes of antihypertensive drugs

are more efficacious in reducing outcomes in younger or

older patients [239]. The latter information confirms what

was already pointed out in the 2007 ESH/ESC guide-

lines, that in the elderly drug treatment can be initiated

with thiazide diuretics, calcium antagonists, angiotensin

receptor antagonists, ACE inhibitors, and b-blockers,

which is in line with general guidelines. The HYVET

adds further evidence to the role of diuretics and ACE

inhibitors. For isolated systolic hypertension of the

elderly, there are three trials [78,81,82] that have used

a diuretic [78] and a calcium antagonist [81,82], respec-

tively, as first-line treatment.

As mentioned previously, a recent reappraisal of trials

[71] has underlined that no single trial on hypertension in

the elderly [76–85] has enrolled patients with grade 1

hypertension (i.e., SBP 140–159 mmHg). Furthermore,

in no placebo-controlled trial of antihypertensive treat-

ment in the elderly [76–84], on-treatment SBP values

have been lowered to less than 140 mmHg, and the only

trial comparing achieved SBP values below and above

140 mmHg [85] is also the only one unable to demon-

strate a benefit of more intense therapy, although the trial

was underpowered because of a limited number of

events. Although clearly not evidence based, the recom-

mendations of the 2007 ESH/ESC guidelines to initiate

antihypertensive therapy in the elderly according to the

same criteria used for younger individuals (i.e., for SBP

�140 mmHg) and to use the same SBP goal as in younger

patients can still be considered as prudent recommen-

dations, particularly when treatment is well tolerated.

However, firm evidence on these two clinically important

issues should be obtained through appropriately designed

new trials.

A reassessment of recommendations on treatment of the

elderly with hypertension is given in Box 7.

Diabetes mellitusReappraisal of antihypertensive treatment trials on dia-

betic patients [71] has strengthened the information pro-

vided in the 2007 ESH/ESC guidelines, by clearly showing

that the evidence in favor of initiating BP-lowering therapy

in diabetic patients with high normal BP is quite scanty,

and that favoring a SBP target below 130 mmHg is almost

nonexistent. Added to the recognized difficulty of achiev-

ing SBP values less than 130 mmHg in diabetic patients

[240], the critical reappraisal of trial data suggests that the

recommendation commonly given to all hypertensives, to


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Box 7. Antihypertensive treatment in the elderly

(1) Since the publication of the last guidelines, evidence from large meta-analyses of published trials confirms

that in the elderly antihypertensive treatment is highly beneficial. The proportional benefit in patients aged

more than 65 years is no less than that in younger patients.

(2) Data from meta-analyses do not support the claim that antihypertensive drug classes significantly differ in

their ability to lower BP and to exert cardiovascular protection, both in younger and in elderly patients. The

choice of the drugs to employ should thus not be guided by age. Thiazide diuretics, ACE inhibitors, calcium

antagonists, angiotensin receptor antagonists, and b-blockers can be considered for initiation and mainten-

ance of treatment also in the elderly.

(3) In the elderly, outcome trials have only addressed patients with an entry SBP at least 160 mmHg, and in no trial

in which a benefit was shown achieved SBP averaged less than 140 mmHg. Evidence from outcome trials

addressing lower entry and achieving lower on-treatment values are thus needed, but common sense

considerations suggest that also in the elderly drug treatment can be initiated when SBP is higher than

140 mmHg, and that SBP can be brought to below 140 mmHg, provided treatment is conducted with particular

attention to adverse responses, potentially more frequent in the elderly.

(4) At variance from previous guidelines, evidence is now available from an outcome trial (HYVET) that

antihypertensive treatment has benefits also in patients aged 80 years or more. BP-lowering drugs should

thus be continued or initiated when patients turn 80, starting with monotherapy and adding a second drug if

needed. Because HYVET patients were generally in good conditions, the extent to which HYVET data can be

extrapolated to more fragile octogenarians is uncertain. The decision to treat should thus be taken on an

individual basis, and patients should always be carefully monitored during and beyond the treatment

titration phase.

lower systolic BP as much as possible below 140 mmHg,

appears realistic and prudent for diabetic patients too.

More complicated is a decision about initiation of pharma-

cological therapy when BP values are still in the high

normal range. If deferring treatment due to the lack of

solid evidence appears legitimate, it also seems reasonable

to give due consideration to data showing prevention

of progression or enhancement of regression of organ

damage, particularly microalbuminuria, which is especially

ominous in diabetic patients because it reflects a greater

risk of end-stage renal disease and cardiovascular events

[241]. In this context, the results of ADVANCE are inter-

esting because a beneficial effect of treatment on micro-

albuminuria and proteinuria was seen at normotensive BP

levels, although normotension was often achieved by the

previous use of antihypertensive drugs, with a clear-cut

reduction in the appearance of new microalbuminuria

(�21%) [123]. This expands the evidence on the ability

of antihypertensive drug treatment to exert a primary

preventive influence against diabetic nephropathy

[86,242,243]. However, the crucial issues of whether to

initiate antihypertensive treatment in diabetic patients

with high normal BP and whether goal BP should be lower

than that recommended in the general hypertensive popu-

lation should be explored through suitably designed

intervention trials.

As to antihypertensive drugs to be preferred in diabetes,

the 2007 ESH/ESC guidelines based their recommen-

dation to use any agent capable of effectively lowering

BP on the evidence of a large meta-analysis showing

substantial equivalence of antihypertensive agents

belonging to various classes in preventing cardiovascular

outcomes in diabetes [186]. This recommendation was


coupled to that of using combinations of drugs that

include an agent blocking the renin–angiotensin system,

because of the particular effectiveness of this type of

agent on renal protein excretion and long-term preser-

vation of renal function. The only large study exclusively

devoted to diabetics completed after the 2007 guidelines,

the ADVANCE trial [88], used the combination of a

diuretic, indapamide, and an ACE inhibitor, perindopril,

often on top of preexisting antihypertensive agents to

produce some further BP decrease associated with a

significant albeit modest reduction (9%) in the combined

endpoint of macrovascular and microvascular compli-

cations, a significant 14% reduction of all cause mortality,

and a significant 21% reduction of renal outcomes, such as

proteinuria, microalbuminuria, doubling of serum creati-

nine, dialysis and renal transplantation. ACCOMPLISH,

though not entirely devoted to diabetes, included 60% of

diabetic patients among the more than 11 000 individuals

enrolled. The study compared the use of an ACE inhibi-

tor, benazepril, in association with either the calcium

antagonist amlodipine or the diuretic hydrochlorothia-

zide and reported superiority of the ACE inhibitor–

calcium antagonist combination [185].

Although diabetic-dependent microvascular compli-

cations are all related to BP within a wide range of values

[244], antihypertensive treatment appears to affect them

in a different fashion. BP reduction has a pronounced

protective effect on renal complications (see Renal dis-

ease section). However, it does not appear to substantially

affect neuropathy [245], whereas data on the ability of

BP-lowering strategies to protect against eye compli-

cations are not consistent. Several years ago, the UKPDS

study [246] reported a reduced incidence of various eye


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Box 8. Antihypertensive treatment in diabetic patients

(1) In diabetic patients, antihypertensive treatment should be always initiated when BP is 140/90 mmHg or more.

Initiation of treatment in the high normal BP range is at present not sufficiently supported by outcome

evidence from trials. It can, nevertheless, be recommended, particularly when microalbuminuria is present,

based on the evidence of its favorable effect on regression and progression of this sign of organ damage.

(2) The BP goal traditionally recommended in diabetes, that is, less than 130/80 mmHg is also not supported by

outcome evidence from trials, and has also been very difficult to achieve in the majority of the patients. Thus, it

appears realistic to only recommend to pursue a sizeable BP reduction without indicating a goal which

is unproven.

(3) Meta-analyses of available trials show that in diabetes all major antihypertensive drug classes protect against

cardiovascular complications, probably because of the protective effect of BP lowering per se. They can thus

all be considered for treatment.

(4) In diabetes, combination treatment is commonly needed to effectively lower BP. A renin–angiotensin receptor

blocker should always be included because of the evidence of its superior protective effect against initiation or

progression of nephropathy.

(5) In hypertensive diabetic patients, tight blood glucose control (HbA1c to 6.5%) is beneficial, particularly on

microvascular complications. Recent evidence suggests that combining effective blood glucose and BP

control increases protection, particularly of the kidney.

(6) Tight blood glucose control should not be pursued abruptly and patients should be monitored closely because

of the increased risk of severe hypoglycemic episodes.

(7) Microvascular complications of diabetes in different organs are differently affected by treatment. Antihy-

pertensive treatment exerts a major protective effect against renal complications, whereas evidence of a

similar effect on eye and neural complications is less consistent.

lesions (and of eye interventions) in hypertensive type 2

diabetic patients under tight versus those under standard

BP control, strengthening the favorable conclusion drawn

from previous smaller or less controlled studies

[86,247,248]. However, no significant beneficial effects

of BP reduction by an ACE inhibitor–diuretic combi-

nation on eye complications has recently been reported in

the hypertensive type 2 diabetic patients of ADVANCE

[88,249], and substantially negative data have also

resulted from the DIRECT trial in normotensive type

1 diabetic patients in whom BP was reduced by an

angiotensin receptor antagonist [250]. Interestingly, the

inconsistency between older and more recent studies

extends to the effect of tight blood glucose control on

eye complications, with favorable reports from UKPDS

[251] and negative ones from ADVANCE [249]. Whether

a protective effect of BP and glucose control on diabetic

retinopathy may only be observed in early phases of the

disease and on appearance rather than progression of

retinopathy remains to be tested by specific trials.

Recommendations on antihypertensive management of

diabetes are summarized in Box 8.

Renal diseaseAs mentioned in previous sections, in the last 2 years,

further evidence has accumulated in favor of targeting

reduction of microalbuminuria and proteinuria, mostly

through blockers of the renin–angiotensin system, in

order to reduce end-stage renal disease and cardiovascu-

lar events. A post hoc analysis of RENAAL data indicates

that the incidence of end-stage renal disease showed an

independent relationship with SBP and albuminuria

reduction, suggesting that improving renal outcomes in


patients with diabetic nephropathy may require a dual

strategy, targeting both BP and albuminuria [228]. Also, in

the type 2 diabetic patients of ADVANCE, urinary protein

excretion (both baseline and on-treatment values) has

been reported to be closely correlated with the primary

outcome of the study (macrovascular and microvascular

events) [18]. On the contrary, ONTARGET has recently

reported that the combination of full doses of the ACE

inhibitor ramipril and the angiotensin receptor antagonist,

telmisartan, though reducing BP a few mmHg more than

therapy with either ramipril or telmisartan and influencing

progress of proteinuria to a slightly but significantly greater

extent, was accompanied by a greater incidence of renal

outcomes (mostly acute dialysis and doubling of serum

creatinine) and by no further reduction of cardiovascular

outcomes [53,191]. As mentioned in a previous section,

only a minority (about 4%) of ONTARGET patients

had overt proteinuria at baseline, whereas worsening of

renal outcomes mostly occurred in the patients without

baseline microproteinuria or macroproteinuria, in whom

changes in urinary protein excretion could only differ to a

minor degree [53]. Finally, the changes in urinary protein

excretion were small and so the between-treatment differ-

ences in renal outcomes were quite infrequent (2.03, 2.21,

and 2.49% with ramipril, telmisartan, and the combination,

respectively). Therefore, ONTARGET patients can

hardly be compared to the more severe nephropathy

cohorts in whom the role of urinary protein excretion in

predicting end-stage renal disease was mostly investi-

gated. When the effects of telmisartan versus placebo

on renal outcomes were studied in the TRANSCEND

trial [108], no significant differences were found as far

as rate of GFR decline and end-stage renal disease is


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concerned [252]. No data on renal outcomes are available

from PROFESS [91], also comparing telmisartan with

placebo.

The 2007 ESH/ESC guidelines [1] shared with other

guidelines [66,253] the recommendation to lower BP

below 130/80 mmHg in renal patients, but it recognized

that evidence from trials having renal patients rando-

mized to more versus less intense BP lowering was

scanty. Little additional evidence, either pro or con this

lower BP target, has been accumulated since. No large

trial completed in the last 2 years focused on patients with

renal dysfunction, and in no instance SBP was brought

below the target of 130 mmHg. A meta-analysis, from

randomized controlled trials of BP lowering in patients

on dialysis, is of interest: BP-lowering treatment was

associated with a significant reduction in cardiovascular

events (29%), all-cause mortality (20%) and cardiovascu-

lar mortality (29%), for a SBP/DBP difference versus

control of �4.5/�2.3 mmHg [254]. Regretfully, no infor-

mation was provided about the absolute BP values

achieved with treatment, although the finding that the

protective effects were significant only in the subgroup of

hypertensive patients may suggest that on-treatment BP

values were not particularly low. The matter is further

complicated by the extensive use of blockers of the

renin–angiotensin system in renal patients. These drugs

are thought to possess specific renal protective properties,

which make the effect attributable to BP reduction more

difficult to unravel.

Cerebrovascular diseaseStroke and transient ischemic attacks

It has been pointed out that the results of the PROGRESS

trial, though clearly showing the benefits of lowering BP in

patients with previous cerebrovascular events [89], cannot

be taken to support a recommendation to initiate BP-

lowering treatment in cardiovascular patients with BP in

the high normal range, as in this trial the benefits of

treatment were seen only in individuals with a baseline

SBP of 140 mmHg and above, who often were on anti-

hypertensive drugs already [90]. Nor can the PROGRESS

data be taken to support a SBP target below 130 mmHg, as

the average SBP achieved on more intense treatment

was 132 mmHg. However, the trial did show that an on-

treatment SBP of 132 mmHg was better than an on-treat-

ment SBP of 141 mmHg, that is, the average SBP of the

placebo patients. In the other trial that first showed the

benefits of BP lowering in patients with cerebrovascular

disease, the PATS study [255], SBP values remained too

high (143 and 149 mmHg in the active and placebo arms

of the trial, respectively) to help clarify when to initiate

treatment and to what level should BP be lowered in

cerebrovascular patients. The same is the case for

ACCESS [256]. Finally, it cannot be denied that the matter

has been further confused by the recent publication of the

negative results of the PROFESS study [91]. In this very


large trial, in patients with previous stroke or transient

ischemic attack, bringing SBP to 136 mmHg by adding

telmisartan, rather than to 140 mmHg by adding placebo,

was not accompanied by any significant reduction in

recurrent strokes or major cardiovascular events. Various

interpretations have been given for these unexpected

negative findings: the small BP difference, in line with

the evidence from the PROGRESS that the small BP

difference in patients on monotherapy also failed to sig-

nificantly reduce outcomes, the short duration of the

follow-up (only 2.5 years), the frequent use of concomitant

therapy (all patients were on antiplatelet agents and half of

them were on lipid-lowering agents), the large dropout of

patients during treatment, and the initiation of treatment

very close to the qualifying cerebrovascular event. The fact

remains that PROFESS has not really helped to clarify the

remaining issues about antihypertensive treatment of the

cerebrovascular patient.

A matter of continuing concern is the optimal BP man-

agement during the acute phase of stroke. The results of a

small trial, the Controlling Hypertension and Hypoten-

sion Immediately Post-Stroke (CHHIPS), suggest a

beneficial impact of administering lisinopril or atenolol

in patients with acute stroke and a SBP more than

160 mmHg [257], but many of the current uncertainties

remain to be clarified.

Cognitive dysfunction and dementia

The 2007 ESH/ESC guidelines stressed the importance

of better clarifying the role of high BP and BP-lowering

treatment on the development of cognitive dysfunction

and dementia but acknowledged that the available

evidence was scanty and confusing [1]. Little further

evidence has been added in the past 2 years, except

for the results of the HYVET on hypertensive octogen-

arians. All patients included in this trial were tested at

baseline and yearly during treatment for cognitive func-

tion with the Mini-Mental State Exam (MMSE), and

patients whose score fell to less than 24 or by more than

three points in any one year, were assessed with further

tests in order to investigate possible incident dementia.

The results showed only a nonsignificant trend for

reduction of both cognitive decline and dementia with

active treatment (hazard ratio 0.86 with 95% confidence

intervals of 0.67–1.09) [258]. Thus, the results of HYVET

cannot help to clarify the matter, but the characteristics of

the study have not been well suited for investigating

dementia: indeed, at baseline, all individuals were rather

healthy and with a good cognitive function and, in

particular, the short duration of the follow-up (only

2 years) was unlikely to allow precise assessment of a

slowly developing condition such as cognitive decline.

The relationship between high BP, antihypertensive

therapy, and cognitive loss is an important issue that

deserves further studies, although it should be recognized

these studies are difficult to design and conduct. In this


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context, it is promising, but by no means conclusive, that

a meta-analysis that included HYVET and other placebo-

controlled trials showed a small and statistically signifi-

cant reduction in the incidence of dementia (�13%) in

the actively treated patients [258].

Coronary heart disease and heart failureIt has already been extensively discussed whether the

current recommendation to lower SBP below 130 mmHg

in patients with concomitant coronary heart disease is

well founded. It has been pointed out that some of the

analyses of recent trials raising the possibility that low

achieved BP values are associated with increased rather

than decreased risk of cardiovascular outcomes [113,115]

are post hoc with well known limitations. It has also been

recognized that a reappraisal of all trials of antihyperten-

sive agents in patients with coronary heart disease has

provided contradictory evidence on the presence or

absence of benefits of lowering SBP below 130 mmHg

[71]. Until firmer evidence is provided by new trials, it

appears reasonable to lower SBP down to the 130–

139 mmHg range in patients with concomitant coronary

heart disease.

The failure to significantly reduce heart failure with

preserved systolic function in the I-PRESERVE study

[259] has to be pointed out. Although this type of heart

failure is most often related to hypertension, in I-PRE-

SERVE randomization to the angiotensin receptor

antagonist, irbesartan, or to placebo, in more than 4000

patients with chronic heart failure and a left ventricular

ejection fraction more than 0.45 (88% of whom had a

history of hypertension) did not show any difference in

the primary endpoint of death from any cause or hospi-

talization for a cardiovascular cause as well as in the

secondary outcome of a composite of heart failure events.

This occurred despite a 3.5/2.0 mmHg SBP/DBP differ-

ence in favor of irbesartan. The negative results of

I-PRESERVE, however, should be seen in the context

of the complex design of the trial, in which a background

of intense antihypertensive therapy, including 25% of

ACE inhibitors (39% during the trial), was maintained,

and initial BP was only 136/79 mmHg, thus further

strengthening the question as to whether lowering SBP

much below 140 mmHg is of any further benefit. It

should be noted that 59% of I-PRESERVE patients were

on antiplatelet agents, 19% on oral anticoagulant therapy,

and 30% on lipid-lowering agents.

The efficacy of angiotensin receptor antagonists in the

prevention of heart failure has come under some discus-

sion also as a result of the TRANSCEND [108] and

PROFESS [91] studies. In both these placebo-controlled

trials, randomization to telmisartan did not reduce the

incidence of hospitalization for heart failure below that

occurring on placebo. In ONTARGET [191], the number

of hospitalizations for heart failure was lower (though not


significantly) with ramipril than with telmisartan. How-

ever, the risk of heart failure in all these trials was rather

low, and definitive conclusions cannot be reached at

present.

Atrial fibrillationThe 2007 ESH/ESC guidelines summarize evidence

from post hoc analyses of heart failure [233,260,261] and

hypertension trials [262,263] showing a lower evidence of

new atrial fibrillation in patients receiving an angiotensin

receptor antagonist (in one trial [260] an ACE inhibitor).

While warning against the possible bias of post hocanalyses, nonetheless the guidelines suggested angioten-

sin receptor antagonists and ACE inhibitors as preferred

drugs in hypertensive patients at risk of developing

atrial fibrillation. A plausible explanation for this was

the association between atrial enlargement and LVH,

the favorable effects of blockers of the renin–angiotensin

system on both cardiac alterations, and the relationship

between LVH regression and reduction in new-onset

atrial fibrillation [49,264]. However, data accumulated

since then do not consistently support this recommen-

dation. Although in ONTARGET [191] new atrial fibril-

lation was slightly less frequent with telmisartan than

with ramipril, placebo-comparisons in TRANSCEND

[108] and PROFESS [91] could not confirm a protective

effect of this angiotensin receptor antagonist against new

onset of atrial fibrillation. In TRANSCEND [108] the

hazard ratio was 1.02, and in PROFESS [91] treatment

discontinuation for atrial fibrillation occurred in 81

patients on telmisartan and in 50 patients on placebo.

In I-PRESERVE [259], atrial arrhythmia is reported in

77 patients on irbesartan and 68 patients on placebo.

The 2007 ESH/ESC guidelines also reported the results

of small studies suggesting that the angiotensin receptor

antagonists may exert favorable effects on recurrent atrial

fibrillation in patients with previous episodes of this

arrhythmia [265,266]. Along the same lines, enalapril

has been reported to facilitate maintenance of sinus

rhythm after conversion treatment [267]. However, the

guidelines stressed the small number of patients in these

studies and concluded that more information was

expected from ongoing specific trials with sufficient

statistical power. Two specific trials have been completed

quite recently (CAPRAF [268], GISSI-AF [269]) and

their results are not supportive of protective effects from

angiotensin receptor antagonists against recurrence of

atrial fibrillation. In GISSI-AF 1442 patients (85% with

a history of hypertension) having had at least two epi-

sodes of atrial fibrillation in the previous 6 months, need

for DC conversion and frequently treated with ACE

inhibitors and class I and III antiarrythmic drugs were

randomized to either valsartan (up to 320 mg/day) or

placebo and followed up for a mean period of 223 days.

Incidence of at least one episode of atrial fibrillation was

51.4% on valsartan and 52.1% on placebo (hazard ratio


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0.99, P¼ 0.84). A recent meta-analysis of all studies of

secondary prevention of atrial fibrillation with blockers of

the renin–angiotensin–aldosterone system appears to

indicate an overall benefits of these agents, however

(R. Schmieder et al., personal communication).

One further point deserves mention. In a recent meta-

analysis [270] including almost 12 000 patients with sys-

tolic heart failure, and therefore at high risk of atrial

fibrillation, b-blockers were found to significantly reduce

(by about 27%) the incidence of atrial fibrillation. A

history of atrial fibrillation and systolic heart failure

may be a specific indication for using b-blockers.

Hypertension in womenThis aspect deserves a brief comment because of the

recent publication of a new meta-analysis from the Blood

Pressure Lowering Treatment Trialists’ Collaboration,

investigating benefit of antihypertensive treatment in

men and women [271]: both BP lowering and reduction

in outcomes were similar in the two sexes and no sex-

related differences in response to various classes of anti-

hypertensive agents could be detected.

Hypertension and erectile dysfunctionErectile dysfunction is a prevalent condition in hyper-

tensive patients and a predictor of future cardiovascular

events. Screening and treatment of erectile dysfunction

improves management of cardiovascular risk factors.

After initiating therapy with phosphodiesterase (PDE)

5 inhibitors, patients are more likely to take antihyper-

tensive medication and BP control is improved [272].

Older antihypertensive drugs (diuretics, b-blockers, cen-

trally acting) exert negative effects, whereas newer drugs

have neutral or beneficial effects (calcium antagonists,

ACE inhibitors, angiotensin receptor antagonists, nebi-

volol) [273].

Treatment of associated risk factorsLipid-lowering agentsThe benefit of combining a statin with antihypertensive

treatment in hypertensive patients was well established

by the ASCOT-LLA study [274], as summarized in the

2007 ESH/ESC guidelines [1]. The negative results

obtained with another statin in the ALLHAT study

[275] can be attributed to insufficient lowering of total

cholesterol (11% in ALLHAT as compared with 20% in

ASCOT). Further analyses of ASCOT have shown the

addition of a statin to the amlodipine-based antihyper-

tensive therapy can reduce the primary cardiovascular

outcome even more markedly than addition of a statin to

the atenolol-based antihypertensive therapy [276,277].

The beneficial effect of statin administration to patients

without previous cardiovascular events has been

strengthened by the findings of the JUPITER study

[278], showing that lowering LDL-cholesterol by 50%

in patients with baseline values less than 130 mg/dl


(3.4 mmol/l), but elevated C-reactive protein (CRP),

reduced cardiovascular events by 44%.

In conclusion, the recommendation given in the 2007

guidelines to consider statin therapy in hypertensive

patients who have an estimated 10-year risk of cardio-

vascular events more than 20% can be reconfirmed, but

the JUPITER study [278] suggests that statin benefits

can be observed also in patients with elevated CRP and at

moderate cardiovascular risk (about 15% cardiovascular

events in 10 years).

Antiplatelet therapyA large meta-analysis has just been published of serious

cardiovascular outcomes and major bleeds in six primary

prevention trials (95 000 individuals at low cardiovascular

risk, 660 000 person-years) and 16 secondary prevention

trials (17 000 individuals at high cardiovascular risk,

43 000 person-years) that compared long-term aspirin

versus control [279]. In the primary prevention trials,

aspirin allocation led to a significant 12% reduction in

serious cardiovascular events (mostly nonfatal myocardial

infarction). However, as a consequence of the overall low

risk of the individuals, absolute event reduction

amounted to only 0.06 events per 100 patient-years,

which was counterbalanced by an absolute increase in

major gastrointestinal and extracranial bleeds of 0.03

bleeds per 100 patient-years. In the secondary prevention

trials, aspirin allocation yielded a greater absolute

reduction in serious cardiovascular events (1.5 event

per 100 patient-years). Although only few secondary

prevention trials carefully reported bleed incidence, data

from trials reporting bleeds suggest an extracranial bleed

excess of no more than 0.2 event per 100 patient-years. It

can, therefore, be concluded that, although adminis-

tration of aspirin has a clear benefit/harm ratio in patients

with cardiovascular disease, there is only a very tiny

excess of benefit over harm in the low-risk patients

included in primary prevention trials.

Of course, the division between primary and secondary

prevention is artificial and arbitrary, and individuals

who have not yet experienced a cardiovascular event

can be at very different levels of total risk. Attention has

been directed to the possible benefits of aspirin in

patients with diabetes but still free of overt cardio-

vascular disease. In the hypertensive patients with dia-

betes in the HOT study, cardiovascular outcome

reduction by aspirin did not achieve statistical signifi-

cance [280,281], nor was a clear benefit seen in diabetic

patients included in other trials [281]. Furthermore, the

recent findings of a large primary prevention study

carried out on diabetic patients in Japan could only show

that low-dose aspirin was associated with a nonsignificant

reduction in cardiovascular outcomes [282]. Therefore,

the benefits of antiplatelet therapy in diabetes remain to

be established.


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The finding that in the HOT study, the greatest benefit of

low-dose aspirin and the best benefit/harm ratio occurred

in patients with serum creatinine more than 1.3 mg/l [280]

has been further elaborated by estimating GFR and

calculating the effects of aspirin versus placebo in three

groups with eGFR 60 ml/min per 1.73 m2 or more, 45–

59 ml/min per 1.73 m2, and less than 45 ml/min per 1.73 m2.

There was a significant trend for increasing reduction in

major cardiovascular events and death with progressive

decline in eGRF, the reduction being particularly marked

in hypertensive patients with eGFR less than 45 ml/min

per 1.73 m2. In this group of patients, the risk of bleeding

was modest as compared with the cardiovascular benefit

[283].

In conclusion, the prudent recommendations of the 2007

ESH/ESC guidelines can be reconfirmed: antiplatelet

therapy, in particular low-dose aspirin, should be pre-

scribed to hypertensive patients with previous cardiovas-

cular events; it can also be considered in hypertensive

patients without a history of cardiovascular disease with

reduced renal function or with a high cardiovascular risk.

In patients receiving aspirin, careful attention should

always be given to the increased possibility of bleeding,

particularly gastrointestinal.

Glycemic controlThe 2007 European guidelines reviewed the data on the

target blood glucose and HbA1c values to be reached in

diabetic patients, an issue of practical importance because

of the highly prevalent association of type 2 diabetes with

hypertension [1]. They indicated a tight blood glucose

control, that is, a glycemic value less than 6.0 mmol/l

(108 mg/dl) and an HbA1c less than 6.5%, to be desirable

as a means to minimize the blood glucose-related macro-

vascular and microvascular complications, as shown in

observational studies [1,284]. Since then, two major

large-scale randomized trials, ADVANCE and ACCORD,

focused on the effects of tight versus standard blood

glucose control in type 2 diabetes, have been published

with inconsistent results [285,286]. In ADVANCE, the

factorial design included assessment of the effects of tight

blood glucose control (goal HbA1c< 6.5%) via adminis-

tration of gliclazide-MR as well as other available pharma-

cological means versus standard blood glucose control in

patients with or without the additional administration of

the indapamide/perindopril combination, as mentioned in

the previous sections. In patients with tight blood glucose

control, the average on-treatment HbA1c was 6.5%, a value

definitely lower than that seen in the standard treated

group (7.3%). This was accompanied by a significant,

although modest, reduction (�10%) in the composite

primary endpoint (microvascular and macrovascular

events) of the trial, which was entirely due to reductions

of the microvascular component, as macrovascular end-

points did not show any significant between-group differ-

ence. In ACCORD, the goal was to lower HbA1c to less


than 6.0%, which led to a 6.5% average on-treatment

HbA1c value reached by patients on tight blood glucose

control (versus 7.5% of the comparison group). This was

associated with a reduction in the incidence of myocardial

infarction, which was accompanied, however, by a signifi-

cant and marked increase (þ35%) in all-cause mortality,

leading the tight blood glucose control arm to a premature

termination. The reasons for the different results of the

two trials are unclear, although the most likely hypothesis

seems to be that, compared with ADVANCE, tight blood

glucose control in ACCORD was obtained much more

abruptly (less than 6 months versus 2 years) by a much

larger use of antidiabetic drugs (thiazolinediones 91.7

versus 16.8%, insulin 77.3 versus 40.5%, and metformin

86.6 versus 73.8%), which might have favored hypoglyce-

mic-related events as indirectly shown by the exceedingly

high number of hypoglycemic episodes reported in the

tight blood glucose as compared to the control group.

The blood glucose goals recommended in the 2007 guide-

lines [1] can thus remain unchanged, although with the

caveat that tight blood glucose control should probably be

pursued gently and values well below 6.5% HbA1c should

be avoided. Further support to this unchanged recommen-

dation comes from the ADVANCE findings that in the

group in which tight blood glucose control was combined

with more intense antihypertensive treatment, the mag-

nitude of the beneficial effects was significantly greater

because of a reduced rate of all-cause mortality as well as of

new-onset microalbuminuria [287]. It should be empha-

sized that in a recent meta-analysis that pooled data from

the four randomized trials so far available on tight blood

glucose control (ADVANCE, ACCORD, UKPDS, and

VADT) [285,286,288,289], this group showed a risk of

severe hypoglycemic episodes that was about 2.5 times

greater than that of the group under standard glucose

control strategy [290]. This calls for the tight blood glucose

control strategy to be applied with close monitoring of

the patients.

The issue of the polypillA recent study [291] has tested the effects on various

cardiovascular risk factors of a pill containing three anti-

hypertensive drugs (an ACE inhibitor, a b-blocker, and a

diuretic), a statin, and aspirin at low dose in individuals

free of cardiovascular disease but just with one cardio-

vascular risk factor. At the end of the 12-week treatment,

there was a reduction in BP, serum cholesterol, and

urinary thromboxane 2 (as an index of antiplatelet action),

as expected from the effects of the single polypill com-

ponents. There was also no increment of the side-effects

due to the individual components when given together in

the single pill. It should be emphasized, however, that

the rationale upon which the polypill has been developed

is not the reasonable one of assembling together several

drugs in order to facilitate treatment in those very high

risk patients requiring multiple therapies [292]. The


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rationale for the polypill, as heralded by Wald and Law

(who have even patented the concept), is that the poly-

pill, containing all types of agents shown capable of

reducing cardiovascular risk, may reduce cardiovascular

risk by more than 80% in all individuals and should be

given to all individuals 55 years and older, irrespective of

previous cardiovascular disease [293]. This can be criti-

cized due to various aspects: as reported previously,

aspirin in low-risk individuals has only small cardiovas-

cular benefits counterbalanced by excess bleeding [279];

antihypertensive agents lower BP only very moderately

in normotensive individuals (as also found in the recent

polypill trial [291]), statins are generally well tolerated

but sometimes accompanied by serious adverse events;

and furthermore, the extent of their benefit in individuals

without any risk factors in unproven. Furthermore, the

concept of treating ‘cardiovascular risk’ as an entity with-

out targeting and monitoring the individual risk factors

appears unsound.

New trials neededIn the past 10–15 years, several trials of antihypertensive

therapy have been completed, but these have mostly

centered on comparisons between different agents or

focused on high cardiovascular risk patients, and have

used so complex designs and so numerous concomitant

therapies as to often make interpretation of their results

difficult and controversial (Box 9). Although these trials

have nevertheless added further useful information,

some major issues have not been explored or have been

insufficiently clarified. As a consequence, many import-

ant decisions on hypertension management are currently

taken only on the basis of post hoc analyses of trial data

relating cardiovascular events to achieved BP values,


Box 9. New trials neededMany important decisions on hypertension management m

from large randomized controlled trials. The following issu

designed trials.

(1) Should antihypertensive drugs be prescribed to all

cardiovascular risk is relatively low or moderate? B

expected in these patients, a placebo-controlled trial

damage of recognized prognostic importance would

(2) Should antihypertensive drugs be prescribed to the

hypertensive treatment achieve a goal of below 140/90

of hard cardiovascular outcomes and could be place

(3) Should antihypertensive drug treatment be started in

vascular or cardiovascular disease when BP is still in t

80 mmHg in these patients? These issues can be ap

evidence is still available on the benefit of lowering

80 mmHg.

(4) What are the lowest safe BP values to achieve by trea

be approached by trials comparing more or less inte

different cardiovascular risk levels.

(5) Are lifestyle measures known to reduce BP also capab

A controlled randomized trial using intermediate end

in patients with high normal BP or grade 1 hyperten

which have notorious limitations because of loss of

randomized design and potential differences in baseline

risk of patients achieving different BP values. Therefore,

it appears highly desirable that recommendations on the

BP threshold for initiation of drug treatment and on BP

targets in different groups of patients are supported by

information from prospective randomized trials designed

to address persisting gaps in current knowledge.

The following issues appear in urgent need to be

approached by simply designed trials:

(1) S

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hig

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nse

le of

poin

sion

hould antihypertensive drugs be prescribed to all

individuals with grade 1 hypertension (SBP 140–

159 mmHg or DBP 90–99 mmHg), even when total

cardiovascular risk is relatively low or moderate? It is

obvious that a randomized trial of active versus

placebo treatment based on hard cardiovascular

outcomes would be very difficult to perform in truly

low cardiovascular risk patients with grade 1

hypertension, because in such patients, the very

low rate of cardiovascular events would make it

necessary to plan a study of a size and/or duration of

unrealistic proportions. However, a placebo-con-

trolled trial using intermediate endpoints such as

LVH, microalbuminuria, or other signs of organ

damage of recognized prognostic importance would

be feasible, ethical, and clinically relevant.

(2) S
hould antihypertensive drugs be prescribed to
the elderly with grade 1 hypertension and should

antihypertensive treatment achieve a goal of below

140/90 mmHg also in the elderly? All successful trials

on elderly hypertensive patients have recruited

patients with SBP 160 mmHg or above, and in most

ed reproduction of this article is prohibited.

currently be taken without the support of evidence

appear in urgent need to be approached by simply

ents with grade 1 hypertension, even when total

se of the very low rate of cardiovascular events

ng intermediate endpoints such as signs of organ

feasible, ethical, and clinically relevant.

erly with grade 1 hypertension, and should anti-

Hg also in the elderly? These trials could make use

ontrolled.

betic patients or in patients with previous cerebro-

igh normal level, and should BP goal be below 130/

ched by placebo-controlled trials because no trial

h normal BP or of achieving BP goals below 130/

t in different clinical conditions? This issue should

BP-lowering treatment strategies in patients with

reducing morbidity and mortality in hypertension?

ts (organ damage) would be feasible and desirable

.

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HJH 201714


of them, the mean entry value has been above

170 mmHg. Likewise, in all trials conducted so far,

the achieved SBP has always been above 140 mmHg.

Because elderly hypertensive patients are character-

ized by a greater cardiovascular risk (and thus by a

greater number of events within the few years of a

trial duration), these trials could make use of hard

cardiovascular outcomes and could be placebo

controlled.

(3) A
ll guidelines suggest to initiate antihypertensive
treatment in diabetic patients or in those with

previous cerebrovascular or cardiovascular disease

when BP is in the high normal level (SBP 130–

139 mmHg or DBP 85–89 mmHg) and recommend

to achieve a goal SBP below 130 mmHg. Although

these recommendations may be wise, they are not

founded on trial evidence. For instance, in no

successful trial of antihypertensive treatment in

diabetic patients has SBP values less than 130 mmHg

been achieved. In most trials on high cardiovascular

risk patients, the randomized treatment was started

on the background of heavy preexisting antihyper-

tensive drug regimens, because the wrong assump-

tion was made that all these patients anyway required

very aggressive BP lowering (the results of taking

wisdom for evidence [71]). In other trials, a large

proportion of patients was concomitantly treated with

agents that may have interfered with the agents to be

tested. For example, in the I-PRESERVE trial [259]

on chronic heart failure with preserved systolic

function, 39% of the patients in whom the effect

of an angiotensin receptor antagonist was tested were

also concurrently treated with an ACE inhibitor,

although no evidence is available that an ACE

inhibitor is beneficial in this type of heart failure.

Here again, a relatively simple trial design specifi-

cally aimed at answering these questions in patients

with previous stroke or coronary event or with

diastolic heart failure would be needed.

(4) I
dentification of the lowest safe BP values on
treatment under different clinical conditions is of

obvious clinical importance, deserving to be addressed

by an ‘ad hoc’ prospective trial that compares more

versus less intense BP-lowering treatment strategies

in patients with different cardiovascular risk levels.

(5) S
everal types of lifestyle changes have been shown to
be capable of reducing BP, but they are unproven to

reduce mortality and morbidity in hypertension.

Although a morbidity/mortality study with lifestyle

changes in grade 1 hypertensive patients may not be

a feasible task, a controlled randomized trial using

intermediate endpoints (organ damage) would be

feasible and desirable.

Acronym listABCD: Appropriate Blood pressure Control in

Diabetes.

yright © Lippincott Williams & Wilkins. Unautho

ACCESS: Acute Candesartan Cilexetil Therapy in

Stroke Survivals.

ACCOMPLISH: Avoiding Cardiovascular Events in

Combination Therapy in Patients Living with Systolic

Hypertension.

ACCORD: Action to Control Cardiovascular Risk in

Diabetes.

ACTION: A Coronary Disease Trial Investigating

Outcome with Nifedipine gastrointestinal therapeutic

system.

ADVANCE: Action in Diabetes and Vascular disease;

Perterax and Diamicron-MR Controlled Evaluation.

ALLHAT: Antihypertensive and Lipid-Lowering

Treatment to Prevent Heart Attack Trial.

ASCOT: Anglo-Scandinavian Cardiac Outcomes Trial.

AUSTRALIAN: Australian Therapeutic Trial in Mild

Hypertension.

BENEDICT: Bergamo Nephrologic Diabetic Compli-

cations Trial.

CAFE: Conduit Artery Function Evaluation.

CAMELOT: Comparison of Amlodipine versus

Enalapril to Limit Occurrences of Thrombosis.

CAPRAF: Candesartan in the Prevention of Relapsing

Atrial Fibrillation.

CASE-J: Candesartan Antihypertensive Survival

Evaluation in Japan.

CHARM: Candesartan in Heart Failure-Assessment

of Reduction in Mortality and Morbidity.

CHHIPS: Controlling hypertension and hypothension

immediately poststroke.

COMET: Carvedilol or Metoprolol European Trial.

COOPER and WARRENDER: Treatment of Hyper-

tension in Elderly Patients in Primary Care.

COOPERATE: Combination Treatment of Angio-

tensin-II Receptor Blocker and Angiotensin-Convert-

ing-Enzyme Inhibitor in Non-Diabetic Renal Disease.

DIRECT: Diabetic Retinopathy Candesartan Trials.

ELSA: European Lacidipine Study on Atherosclerosis.

EUROPA: European Trial on Reduction of Cardiac

Events with Perindopril in Stable Coronary Artery

Disease.

EWPHE: European Working Party on High Blood

Pressure in the Elderly.

FEVER: Felodipine Event Reduction.

GEMINI: Glycemic Effect in Diabetes Mellitus:

Carvedilol–Metoprolol Comparison in Hypertensives.

GISSI-AF: Gruppo Italiano per lo Studio della Soprav-

vivenza nell’Infarto Miocardico–Atrial Fibrillation.

HDFP: Hypertension Detection and Follow-up

Program.

HOPE: Heart Outcomes Prevention Evaluation.

HOT: Hypertension Optimal Treatment Study.

HYVET: Hypertension in the Very Elderly Trial.

IDNT: Irbesartan Diabetic Nephrophaty Trial.

INSIGHT: International Nifedipine GITS Study:

Intervention as a Goal in Hypertension Treatment.

INVEST: International Verapamil SR/Trandolapril

study.


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HJH 201714


I-PRESERVE: Irbesartan in Heart Failure with

Preserved Systolic Function.

JATOS: Japanese Trial to Assess Optimal Systolic

Blood Pressure in Elderly Hypertensive Patients.

JUPITER: Justification for the Use of Statins in

Primary Prevention: An Intervention Trial Evaluating

Rosuvastatin.

LIFE: Losartan Intervention For Endpoint reduction

in Hypertension.

MDRD: Modification of Diet in Renal Disease.

MICROHOPE: Microalbuminuria, Cardiovascular

and Renal Outcomes in the Heart Outcomes Preven-

tion Evaluation.

MRC: Medical Research Council Trial of Treatment

of Mild Hypertension.

MRC elderly: Medical Research Council Trial of

Treatment of Hypertension in Older Adults.

ONTARGET: Ongoing Telmisartan Tlone and in

combination with Ramipril Global Endpoint Trial.

OSLO: Oslo Study of Treatment of Mild Hyper-

tension.

PAMELA: Pressioni Arteriose Monitorate E Loro

Associazioni.

PATS: Post-stroke Antihypertensive Treatment Study.

PEACE: Prevention of Events with Angiotensin

Converting Enzyme Inhibition.

PHARAO: prevention of hypertension with the

angiotensin-converting enzyme inhibitor ramipril in

patients with high-normal blood pressure.

PHYLLIS: Plaque Hypertension Lipid Lowering

Italian Study.

PREVEND: Prevention of Renal and Vascular End

Stage Disease.

PREVENT: Prospective Randomized Evaluation of

the Vascular Effects of Norvasc Trial.

PROFESS: Prevention Regimen for Effectively

Avoiding Second Strokes.

PROGRESS: Perindopril Protection against Recur-

rent Stroke Study.

RENAAL: Reduction of Endpoints in Noninsulin

dependent diabetes mellitus with the Angiotensin II

Antagonist Losartan.

SCOPE: Study on Congnition and Prognosis in the

Elderly.

SCORE: Systematic Coronary Risk Evaluation.

SENIORS: Study of the Effects of Nebivolol Inter-

vention on OUtcomes and Rehospitalisation in Seniors

with heart failure.

SHEP: Systolic Hypertension in the Elderly Program.

STOP: Swedish Trial in Old Patients with Hyper-

tension.

Syst-China: Systolic Hypertension in China.

Syst-Eur: Systolic Hypertension in Europe.

TNT: Treating to New Targets.

TRANSCEND: Telmisartan randomized assessment

study in ACE-I intolerant subjects with cardiovascular

disease.

TROPHY: Trial of Preventing Hypertension.

yright © Lippincott Williams & Wilkins. Unautho

UKPDS: United Kingdom Prospective Diabetes

Study.

VADT: Veterans Affairs Diabetes Trial.

Val-HeFT: Valsartan Heart Failure Trial.

VALIANT: Valsartan In Acute Myocardial Infarction

Trial.

VALUE: Valsartan Antihypertensive Long-term Use

Evaluation.

AcknowledgementWe are grateful to Fosca Quarti-Trevano, MD, Ms Clara

Sincich, Ms Cinzia Tiberi and Ms Donatella Mihalich for

their valuable help.

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